JP6545197B2 - Novel pyrazolopyrimidine derivatives and their use as MALT1 inhibitors - Google Patents

Description

  The present invention describes novel pyrazolo-pyrimidine derivatives which generally interact with the proteolytic and / or autoproteolytic activity of MALT1 and in particular can inhibit said activity. The invention further describes the synthesis of said novel pyrazolo-pyrimidine derivatives, in particular their use as medicaments by interacting with the proteolytic and / or autoproteolytic activity of MALT1.

  The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof and its use in the treatment of a wide range of diseases or disorders, in particular MALT1 related diseases or disorders. This includes, but is not limited to, rheumatoid arthritis, multiple sclerosis, autoimmune disorders and inflammatory diseases such as systemic lupus erythematosus or vasculitis conditions, chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma and others It may include cancers or solid tumors of hematopoietic origin including B cell lymphomas of

  The essential role of MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) in affecting the immune response has been described in a number of publications. For example, Rudi Beyaert et al. (WO 2009/065897) describes certain compounds as inhibitors of the proteolytic and / or autoproteolytic activity of MALT1.

  Studies in BCL10 and MALT1 deficient mice appear to suggest their essential role in the signal transduction cascade from the antigen receptor to the transcription factor NFkB. Furthermore, chromosomal translocations that lead to overexpression of BCL10 and MALT1, or the production of the constitutively active fusion protein API2-MALT1 appear to lead to uncontrolled and stimulus-independent activation of NFkB. Inhibitors of the proteolytic activity of MALT1 have been described along with their activity in preclinical lymphoma models (Vincendeau et al. Int. J. Hematol. Oncol. 2013, 2, 409).

  Furthermore, certain publications have identified MALT1 and its proteins in signal transduction cascades triggered by native cell receptor-like dectin receptors, and in G-protein coupled receptors in many cell types. It seems to suggest an important role of degradation function.

  Thus, it seems desirable to discover and develop potent MALT1 inhibitors that contain valuable pharmacological properties.

  The present invention describes novel pyrazolo-pyrimidine derivatives according to formula (I), or pharmaceutically acceptable salts thereof, as potent inhibitors of MALT1 and, therefore, they constitute a broad spectrum of diseases or It may be useful in the treatment of disorders, in particular MALT1 related diseases or disorders. This may include, but is not limited to, autoimmune disorders and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitis conditions. These include airway diseases such as allergic diseases, asthma and chronic obstructive pulmonary disease (COPD), or conditions caused by delayed or immediate hypersensitivity reactions and anaphylaxis, acute or chronic transplant rejection or graft versus host disease, chronic Further included are cancers or solid tumors of hematopoietic origin, including myeloid leukemia, myeloid leukemia, non-Hodgkin's lymphoma and other B cell lymphomas.

  More particularly, in embodiment 1, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;

(In the formula,
R 1 is halogen, cyano or C ₁ -C ₃ alkyl optionally substituted by halogen,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times; C ₁ -C ₆ alkyl, N, N-di-C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkoxy-C _1- C ₆ when a C ₃ -C ₆ cycloalkyl substituted by a alkyl, and / or two of the substituents of the optional one with the atoms to which they are bonded It is in the 1 to 2 ring of 4-6 membered containing O atoms or may form a saturated heterocyclic ring _spirocyclic, C 3 -C _{6 cycloalkyl;} C 1 -C Phenyl optionally substituted by ₆ alkoxy; 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O (the said ring is optionally substituted by amino or hydroxy Optionally substituted by C ₁ -C ₆ alkyl); Rg; or N, N-di-C ₁ -C ₆ alkylaminocarbonyl,
R g is a 5- to 6-membered heterocyclic ring having 1 to 3 hetero atoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ to C ₆ alkyl, optionally substituted by C ₁ -C ₆ alkoxy-carbonyl),
R is phenyl which is independently substituted two or more times by Ra, 2-pyridyl which is independently substituted one or more times by Rb, one or more times independently substituted by Rc 3-pyridyl, or 4-pyridyl independently substituted one or more times by Rd,
Ra is, independently of one another, a 5- to 6-membered having 1 to 2 heteroatoms selected from halogen; cyano; -COOC ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; halogen or N and O C ₁ -C ₆ alkyl optionally substituted by heterocyclyl ring (the said ring is optionally substituted by C ₁ -C ₆ alkyl); 1-3 selected from N and O A 5- to 6-membered heteroaryl ring having a heteroatom (the said ring being C ₁ -C ₆ alkyl optionally substituted by amino, amino or hydroxy, or N-mono- or N, N-di-C ₁ is optionally substituted) by -C ₆ alkylaminocarbonyl,
And / or two Ra, together with the ring atom to which they are attached, form a 5- to 6-membered heterocyclic or heteroaromatic ring having 1 to 2 N atoms Well, any such ring is optionally substituted by C ₁ -C ₆ alkyl or oxo,
R b, R c and R d independently of one another are halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di -C ₁ -C ₆ alkylamino; halogen or _C 1 -C ₆ alkyl optionally substituted by phenyl; 5-6 membered heteroaryl ring (wherein the ring having 1-3 N atoms, amino or C ₁ -C ₆ alkyl, optionally substituted by hydroxy, or optionally substituted by mono- or di-N-C ₁ -C ₆ alkylaminocarbonyl); O-Rh; or Rh,
Rh is a 5-6 membered heterocyclyl ring with 1 to 4 heteroatoms selected from N, O and S, said ring being optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo )).

  In its broadest embodiment (embodiment 1), the present invention relates to a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described above in the Summary of the Invention section.

Embodiment 2 is
R1 is halogen,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
2-pyridyl independently substituted one or more times by R b, 3-pyridyl independently substituted one or more times independently by R c, or one or more times independently independently by Rd Substituted 4-pyridyl,
R b, R c and R d are as defined in embodiment 1;
It relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

The third embodiment is
R1 is cyano,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
2-pyridyl independently substituted one or more times by R b, 3-pyridyl independently substituted one or more times independently by R c, or one or more times independently independently by Rd Substituted 4-pyridyl,
R b, R c and R d are as defined in embodiment 1;
It relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

The fourth embodiment is
R ₁ is C ₁ -C ₃ alkyl optionally substituted by halogen,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
2-pyridyl independently substituted one or more times by R b, 3-pyridyl independently substituted one or more times independently by R c, or one or more times independently independently by Rd Substituted 4-pyridyl,
R b, R c and R d are as defined in embodiment 1;
It relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

The fifth embodiment is
R 1 is chloro and the remaining substituents are as defined in embodiment 1 or 2.
It relates to the compound of embodiment 1 or 2 or a pharmaceutically acceptable salt thereof.

The sixth embodiment is
R1 is chloro,
R is 2-pyridyl independently substituted one or more times by R b, and the remaining substituents are as defined in embodiment 2.
It relates to the compound of embodiment 2 or a pharmaceutically acceptable salt thereof.

The seventh embodiment is
R1 is chloro,
R is 3-pyridyl independently substituted one or more times by R c, and the remaining substituents are as defined in embodiment 2.
It relates to the compound of embodiment 2 or a pharmaceutically acceptable salt thereof.

The eighth embodiment is
R1 is chloro,
R is 4-pyridyl independently substituted one or more times by Rd, and the remaining substituents are as defined in embodiment 2.
It relates to the compound of embodiment 2 or a pharmaceutically acceptable salt thereof.

The ninth embodiment is
R is 4-pyridyl independently substituted one or more times by Rd, and the remaining substituents are as defined in embodiment 4.
It relates to the compound of embodiment 4 or a pharmaceutically acceptable salt thereof.

  Embodiment 10 relates to the compound of embodiment 1, 5, 6, 7, 8 or 9, or a pharmaceutically acceptable salt thereof, wherein the halogen is independently selected from fluoro and chloro.

  Embodiment 11 relates to the compound of embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro.

Embodiment 12 relates to the compound of embodiment 1, 4 or 9, or a pharmaceutically acceptable salt thereof, wherein R ₁ is C ₁ -alkyl optionally substituted by fluoro.

  Embodiment 13 relates to the compound of embodiment 1, 4 or 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

Embodiment 14 is a substituted group Rb, the Rc and / or Rd, independently of one another, halogen, _cyano, C 1 -C ₆ alkoxy; _C 1 -C ₆ alkyl optionally substituted by halogen or phenyl; or 5 to 6 membered heteroaryl ring containing 1 to 3 N atoms, said ring being C _{1 to} C ₆ alkyl optionally substituted by amino or hydroxy, or mono- or di-N-C ₁ it is optionally substituted) by -C ₆ alkylaminocarbonyl, compound of embodiment 5, 6, 7, 8 or 9, or a pharmaceutically acceptable salt thereof.

The fifteenth embodiment is
R 1 is halogen, cyano or C ₁ -C ₃ alkyl optionally substituted by halogen,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times; C ₁ -C ₆ alkyl, N, N-di-C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkoxy-C _1- a C ₃ -C ₆ cycloalkyl optionally substituted by C ₆ alkyl, or two of the substituents of the optionally it together with the atom to which they are attached Te, 1-2 O atoms 4-6 membered cyclization or may form a saturated heterocyclic ring spirocyclic _containing, C 3 -C _{6 cycloalkyl;} C 1 -C ₆ alkoxy Optionally substituted phenyl; 1 to 3 heteroatoms selected from N and O, optionally substituted by C ₁ -C ₆ alkyl optionally substituted by amino or hydroxy A substituted 5 to 6 membered heteroaryl ring; R g; or N, N-di-C ₁ -C ₆ alkylaminocarbonyl,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
R is phenyl independently substituted two or more times with Ra,
Cyano, -COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or a 5- to 6-membered heterocyclic ring containing 1-2 N atoms (wherein each Ra is independently of each other, halogen; cyano; Said ring is C ₁ -C ₆ alkyl optionally substituted by C ₁ -C ₆ alkyl) 5-6 membered heteroaryl ring containing 1 to 3 N atoms (The ring is optionally substituted by C ₁ -C ₆ alkyl optionally substituted by amino, amino or hydroxy, or N-mono- or N, N-di-C ₁ -C ₆ alkylaminocarbonyl Yes),
And / or two Ra together with the ring atom to which they are attached form a 5- to 6-membered heterocyclic or heteroaromatic ring containing 1-2 N atoms, such Either ring is optionally substituted by C ₁ -C ₆ alkyl or oxo
It relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

The sixteenth embodiment is
R1 is halogen,
R is phenyl independently substituted two or more times with Ra,
5-, _6- , or 6-membered heterocyclic rings each containing, independently of one another, halogen; cyano; -COOC ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; fluoro or 1 to 2 N atoms C ₁ -C ₆ alkyl optionally substituted by heterocyclyl with C ₁ -C ₆ alkyl; 5- to 6-membered heteroaryl rings containing 1 to 3 N atoms The ring is optionally substituted by C ₁ -C ₆ alkyl optionally substituted by amino, amino or hydroxy, or N-mono- or N, N-di-C ₁ -C ₆ alkylaminocarbonyl ) And
The remaining substituents are as defined in Embodiment 1.
Embodiment 21 relates to the compound of embodiment 1 or 15, or a pharmaceutically acceptable salt thereof.

  Embodiment 17 relates to the compound of embodiment 15 or 16 or a pharmaceutically acceptable salt thereof, wherein R 1 is chloro.

  Embodiment 18 relates to the compound of embodiment 15 or 16 or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro.

  Embodiment 19 relates to the compound of embodiment 15, or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

  Embodiment 20 relates to the compound of embodiment 15, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyano.

Embodiment 21 is that the compound is
(S) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoro) Methyl) -1,2-dihydropyridin-3-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxy-2) -Methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (7- (1-Methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea ;
(S) -1- (2-Fluoro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
(S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-cyanopyridin-3-yl) urea;
(S) -1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-methoxy-6- (2H-1,2,2) 3-Triazol-2-yl) pyridin-3-yl) urea;
(S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2-chloropyridin-4-yl) urea;
(S) -Methyl 3-chloro-5- (3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) ureido) benzoate;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methoxypropan-2-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (2-methoxypropan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methylcyclopropyl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1-methylcyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (3-cyano-4- (3-methyl-1H-1,2,4-triazole) 1-yl) phenyl) urea;
1- (3-Chloro-4- (2H-1,2,3-triazol-2-yl) phenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine-6- Il) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] Pyrimidin-6-yl) urea;
1- (5-chloro-6- (4-methyl-2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,1] 5-a] pyrimidin-6-yl) urea;
1- (4- (2-aminopyrimidin-4-yl) -3-chlorophenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-1-methyl-6-oxo-2- (1H-pyrazol-1-yl) -1,6-dihydropyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo) [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-ethoxypyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-bromopyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (6- (1,1-dioxideisothiazolidin-2-yl) -5- (tri) Fluoromethyl) pyridin-3-yl) urea;
1- (3-Chloro-4- (3- (hydroxymethyl) -5-methyl-1H-pyrazol-1-yl) phenyl) -3- (2-chloro-7-iso-propylpyrazolo [1,5] -A] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (1-methyl-1H-pyrazol-5-yl) pyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine- 6-yl) urea;
1- (2-Chloro-7-isopropyl pyrazolo [1,5-a] pyrimidin-6-yl) -3- (3,5-dichloro-4- (2H-1,2,3-triazole-2-) Yl) phenyl) urea;
1- (5-Chloro-2-oxoindoline-7-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoro-methyl) -1,2-) Dihydropyridin-3-yl) urea;
1- (5-Chloro-2-((1-methylpyrrolidin-3-yl) oxy) -6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- ( 2-chloro-7-isopropyl pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (7- (tert-Butyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-chloro-6- (2H-1,2,3-triazole-2-) Y) pyridin-3-yl) urea;
1- (7- (sec-butyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-chloro-6- (2H-1,2,3-triazole-2-) Y) pyridin-3-yl) urea;
1- (2-Chloro-7- (2-methyltetrahydrofuran-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoro-methyl) pyridin-4-yl )urea;
(R) -1- (2-Chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoro-methyl) pyridine -4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-cyclobutylpyrazolo [1,5-a ] -Pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (2- (2-)) Methoxy-ethoxy) -ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (1- (2-methoxyethoxy) -ethyl) -pyrazolo- [1,5- a) Pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1- (2-methoxyethoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl)- Pyridin-4-yl) urea;
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (2- (2-)) Methoxy-ethoxy) -ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,4-dioxane-2-yl) )-Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxypropane-) 2-yl) -pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxypropane-) 2-yl) -pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) -Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) -pyridin-4-yl )urea;
(R) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoro) Methyl) -1,2-dihydropyridin-3-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (methoxy (phenyl) methyl) -pyrazolo [ 1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methoxymethyl) cyclobutyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1- (methoxymethyl) cyclobutyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea ;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-cyclopropylpyrazolo [1,5-a ] Pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methoxyphenyl) pyrazolo [1,1] 5-a] pyrimidin-6-yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (tetrahydrofuran-2-yl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methyltetrahydro-2H-pyran) 4-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxyethyl) pyrazolo [ 1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (tetrahydrofuran-3-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (tetrahydro-2H-pyran-4-yl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (methoxymethyl) pyrazolo [1,5- a) Pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((tetrahydro-2H-pyran-4-) (I) methyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (isopropoxymethyl) pyrazolo [1,5] -A] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-methylpyrazolo [1,5-a] pyrimidine- 6-yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (furan-2-yl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,3-dimethoxypropyl) pyrazolo [ 1,5-a] pyrimidin-6-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (7- (1- (benzyloxy) ) Ethyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) urea;
tert-Butyl 2- (2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ureido) pyrazolo [1,5 -A] pyrimidin-7-yl) morpholine-4-carboxylate;
1- (7- (3-oxabicyclo [3.1.0] hexan-6-yl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-chloro-6-) Methoxypyridin-3-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (5-oxaspiro [2.4] heptane) -1-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (pyridin-4-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ureido) -N, N-dimethylpyrazolo [1,1 5-a] pyrimidine-7-carboxamide;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (7- (1-methoxyethyl) -2-methyl -Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-methyl-7- (1-methylcyclopropyl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-methyl-7- (1-methylcyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxy-2) -Methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine- 4-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methoxymethyl) cyclopropyl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1- (methoxymethyl) cyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (7- (1- (methoxymethyl) cyclopropyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (7- (1- (Methoxymethyl) cyclopropyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea ;
1- (2-Chloro-7- (2- (tetrahydro-2H-pyran-4-yl) propan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (2- (2) Trifluoromethyl) pyridin-4-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxypropane-2-) Yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (2- (2-)) (Dimethylamino) ethoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((4-methylmorpholin-3-yl) ) Methyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methylpiperidine-) 2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-((R) ) -2-Methoxy-propoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methyl-1H-imidazole-2) -Yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (5-methyltetrahydrofuran-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) cyclopropyl)) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5- (difluoromethyl) -6- (2H-1) 2,3-Triazol-2-yl) pyridin-3-yl) urea;
1- (2-Chloro-7- (methoxy (tetrahydro-2H-pyran-4-yl) methyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine -4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2- (methoxymethyl) tetrahydrofuran-2) -Yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (difluoromethyl) pyridin-4-yl) urea ;
(S) -1- (5-Chloro-6- (difluoromethoxy) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6 -Yl) urea;
(S) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-fluoro-7- (1) -Methoxy-ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-fluoro-7- (1-methoxyethyl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-cyano-7- (1-methoxy-ethyl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (difluoromethoxy) pyridin-3-yl) -3- (2-chloro-7- (1- (2-methoxyethoxy) ethyl) pyrazolo [1,5- a) Pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((1R, 2R) -1,2) -Dimethoxy-propyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-2- (2- (dimethylamino) ethoxy) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5- a) Pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( R) -Tetrahydro-furan-3-yl) oxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( S) -Tetrahydro-furan-3-yl) oxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( S) -Tetrahydro-furan-3-yl) methoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( R) -Tetrahydro-furan-3-yl) methoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-methyl-7- (2-methyltetrahydrofuran-2-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2-cyanopyridin-4-yl) urea;
1- (2-Chloro-7- (2- (methoxymethyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5- (trifluoromethyl) pyridine-3 -Yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethyl-) Amino) cyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxy) -Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1,2-dimethoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
(S) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxy-propan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxy-propan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) pyridin-4-yl) -3- (2-chloro-7-isopropylpyrazolo [1,1] 5-a] pyrimidin-6-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Hydroxy-ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-hydroxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-2-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methylmorpholin-2-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (4- (4- (aminomethyl) -1H-pyrazol-1-yl) -3-chlorophenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6- Il) urea;
1- (6- (4- (aminomethyl) -1H-pyrazol-1-yl) -5-chloropyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a ] Pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
2- (3- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) ureido) -4- (trifluoromethyl) pyridine 1-oxide;
(R) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-3-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methyl-1) -(Methyl-amino) propyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methylmorpholin-3-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxy) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxy) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea
In particular the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

Embodiment 22 is
R1 is fluoro,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
A 5- to 6-membered heterocyclic ring wherein Rg is selected from N and O having 1 to 3 hetero atoms (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ to C ₆ alkyl, optionally substituted by C ₁ -C ₆ alkoxy-carbonyl),
R is 2-pyridyl substituted one or more times with R b,
R b independently of one another of halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di-C _1- C ₆ alkylamino; C _{1 to} C ₆ alkyl optionally substituted by halogen or phenyl; 5 to 6 membered heteroaryl ring having 1 to 3 N atoms (the said ring is optionally substituted by amino or hydroxy A substituted C ₁ -C ₆ alkyl, or optionally substituted by mono- or di-N-C ₁ -C ₆ alkylaminocarbonyl); O-Rh; or Rh,
A 5- to 6-membered heterocyclyl ring with 1 to 4 heteroatoms selected from N, O and S, wherein said ring is optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo ),
It relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

Embodiment 23 is
R1 is fluoro,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
R is 3-pyridyl which is substituted one or more times by R c,
R c independently of one another of halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di-C _1- C ₆ alkylamino; C _{1 to} C ₆ alkyl optionally substituted by halogen or phenyl; 5 to 6 membered heteroaryl ring having 1 to 3 N atoms (the said ring is optionally substituted by amino or hydroxy A substituted C ₁ -C ₆ alkyl, or optionally substituted by mono- or di-N-C ₁ -C ₆ alkylaminocarbonyl); O-Rh; or Rh,
5- to 6-membered heterocyclyl having 1 to 4 heteroatoms, wherein Rh is selected from N, O and S (the said ring is optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo) Is
It relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

Embodiment 24 is
R1 is fluoro,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
R is 4-pyridyl substituted one or more times by Rd,
Rd is, independently of one another, halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di-C _1- C ₆ alkylamino; C _{1 to} C ₆ alkyl optionally substituted by halogen or phenyl; 5 to 6 membered heteroaryl ring containing 1 to 3 N atoms (the said ring is optionally substituted by amino or hydroxy _C 1 -C ₆ alkyl or mono-, substituted by - optionally substituted by or di _-N-C 1 ~C ₆ alkylaminocarbonyl); a or Rh,; O-Rh
5 to 6 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O and S (wherein the ring is optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo) ),
It relates to the compound of embodiment 1 or a pharmaceutically acceptable salt thereof.

  Embodiment 25 relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the embodiments 1 to 24, and one or more pharmaceutically acceptable carriers.

  Embodiment 26 relates to a combination comprising a therapeutically effective amount of a compound according to any one of the embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active coagents. .

  Embodiment 27 is a method of modulating MALT1 activity in a subject, said subject comprising a therapeutically effective amount of a compound according to any one of the embodiments 1-24, or a pharmaceutically acceptable salt thereof. The method relates to the step of administering.

  Embodiment 28 is a compound according to any one of the embodiments 1-24, or a pharmaceutically acceptable compound thereof, for use as a medicament, in particular for use as a medicament acting as a MALT1 inhibitor. It is about salt.

Definitions As used herein, the term "C ₁ -C ₆ alkyl" has up to 6 carbon atoms refers to a hydrocarbon moiety fully saturated to have branched or unbranched. Unless otherwise indicated, C ₁ -C ₆ alkyl refers to a hydrocarbon moiety having ₁ to ₆ carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl , N-hexyl and the like.

As used herein, the term "C ₁ -C ₆ alkylene" refers to a 1-6 carbon atoms, the fully saturated and has a branched or unbranched divalent hydrocarbon moiety. Thus, the terms "C _1-4 alkylene", "C _1-3 alkylene" and "C _1-2 alkylene" will be interpreted. Representative examples of C ₁ ~ ₆ alkylene, but are not limited to, methylene, ethylene, n- propylene, iso - propylene, n- butylene, sec- butylene, iso - butylene, tert- butylene, n- pentylene , Isopentylene, neopentylene, and n-hexylene.

As used herein, the term "C ₁ -C ₆ alkoxy" refers to an alkyl -O-, where alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms.

As used herein, C ₁ term "C ₁ -C ₆ alkyl which is optionally substituted by halogen", which may be substituted by one or more halogens, as defined above ~C refers to the ₆ alkyl. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoro Propyl and 1-bromomethyl-2-bromoethyl are included.

As used herein, the term "C ₁ -C ₆ alkyl optionally substituted by hydroxyl" may be C ₁ as defined above optionally substituted by one or more hydroxy ~C refers to the ₆ alkyl. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, 2,3-dihydroxy-propyl and the like.

As used herein, the term " _diC1-6 alkylamino" refers to _a moiety of the formula -N ( _Ra ) -Ra, wherein _Ra may each be the same or different. It is _C1-6 alkyl defined. Similarly, the term "mono C _1-6 alkylamino" refers to _a moiety of the formula -N (H) -R _a , wherein R _a may be the same or different, C, _{1 to 6} alkyl.

As used herein, the term "C ₃ -C ₆ cycloalkyl" refers to consist 3-6 carbon atoms a saturated monocyclic hydrocarbon group. Cycloalkyl can also be called carbocyclic ring, and conversely additionally refers to the number of carbon atoms present. Unless otherwise indicated, it refers to cyclic hydrocarbon groups having between 3 and 6 ring carbon atoms, or between 3 and 4 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

  As used herein, the terms "halogen" or "halo" refer to fluoro, chloro, bromo and iodo, and in particular may refer to chloro, and also in particular to fluoro.

  As used herein, the term "heterocyclyl", unless otherwise indicated, refers to a saturated or partially saturated heterocyclic group, preferably a monocyclic or polycyclic ring (polycyclic ring In particular, bicyclic, tricyclic or spirocyclic rings), 3 to 24, more preferably 4 to 16, most preferably 5 to 10, and most preferably 5 to 6 And one or more, preferably 1 to 4 and especially 1 to 2 ring atoms are hetero atoms (thus, the remaining ring atoms are carbon). . The attached ring (i.e., the ring attached to the molecule) preferably has 4 to 12, especially 5 to 7 ring atoms. The term heterocyclyl excludes heteroaryl. The heterocyclic group can be attached to a heteroatom or carbon atom. Heterocyclyl can include fused or bridged rings, as well as spirocyclic rings. Examples of the heterocyclic ring include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran Dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine and the like.

  Substituted heterocyclyl is a heterocyclyl group which is independently substituted with 1 to 4 substituents, such as 1 or 2 or 3 or 4 substituents.

  As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic or bicyclic or tricyclic aromatic ring system having 1 to 8 heteroatoms. Typically, heteroaryl is a 5 to 10 membered ring system (eg, a 5 to 7 membered monocycle, or an 8 to 10 membered bicyclic), or a 5 to 7 membered ring system. Exemplary heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4-, or 5- Pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5 -1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5 -Pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl are included.

  The term "heteroaryl" also refers to groups wherein the heteroaromatic ring is fused to one or more aryl rings, alicyclic rings, or heterocyclyl rings, and the radical or point of attachment is the heteroaromatic ring. It is above. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl. , 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6 -, 7- or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7- or 8 -Phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6 -, 7-, Or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4 aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1 -, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7 -, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6- 8-, 9- or 10-phenatrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl 2-, 3-, 4-, or thieno [2 , 3-b] furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7 H-pyrazino [2,3-c] carbazolyl, 2-, 3 -, 5-, 6-, or 7-2H-furo [3,2-b] -pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido [2,3- d] -o-Oxazinyl, 1-, 3-, or 5- 1 H-pyrazolo [4, 3-d] -oxazolyl, 2-, 4-, or 54H-imidazo [4, 5-d] thiazo Ryl, 3-, 5-, or 8-pyrazino [2,3-d] pyridazinyl, 2-, 3-, 5-, or 6-imidazo [2, 1-b] thiazolyl, 1-, 3-, 6 -, 7-, 8- or 9-furo [3,4-c] cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11- 4H-pyrido [2,3-c] carbazolyl, 2-, 3-, 6-, or 7-imidazo [1,2-b] [1,2,4] triazinyl, 7-benzo [b] thienyl, 2 -, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzoimidazolyl, 2-, 4-, 4-, 5-, 6- Or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzooxapinyl, 2-, 4-, 5-, 6 , 7- or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1 H-pyrrolo [1,2-] b] [2] Benzazapinyl is included. Exemplary fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo [B] Thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzoimidazolyl, and 2-, 4-, 5-, 6- or 7-benzothiazolyl is included. Substituted heteroaryl is a heteroaryl group containing one or more substituents.

  As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion. Typically, aryl is mono-, bi- or tricyclic aryl having 6 to 20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent which can be a single aromatic ring or a polyaromatic ring fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

Substituted aryl, hydroxyl, thiol, cyano, _nitro, C 1 -C ₄ - _alkyl, C 1 -C ₄ - _alkenyl, C 1 -C ₄ - _alkynyl, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - _thioalkyl, C 1 -C ₄ - _alkenyloxy, C 1 -C ₄ - alkynyloxy, _halogen, C 1 -C ₄ - alkylcarbonyl, _carboxy, C 1 -C ₄ - alkoxycarbonyl, _amino, C 1 -C ₄ - Alkylamino, di-C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -alkylaminocarbonyl, di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C _4- alkylcarbonyl (C ₁ -C ₄ -alkyl) amino, sulfonyl, sulfamoyl, alkylsulfamoyl, An aryl group substituted by 1 to 5 (such as 1 or 2 or 3) substituents selected independently from the group consisting of C ₁ -C ₄ -alkylaminosulfonyl, as described above each hydrocarbon radical (e.g., alkyl, alkenyl, alkynyl, alkoxy residues), halogen, hydroxyl or C ₁ -C 4 _- is independently selected at each occurrence from alkoxy groups, one or more residues And may be further substituted.

  As used herein, the term pyridine or pyridyl, which is optionally substituted by hydroxy, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, refers to hydroxy-pyridine or hydroxy-pyridyl respectively It can include pyridone or its tautomers such as pyridone-yl.

  As used herein, the term pyridin or pyridyl optionally substituted by oxo, such as 2-pyridyl, 3-pyridyl or 4-pyridyl, refers to pyridone or pyridone-yl, respectively, and is hydroxy-pyridine respectively Or a tautomer thereof such as hydroxy-pyridyl, provided that the said tautomer is a condition that can be obtained. Pyridine or pyridyl optionally substituted by oxo can further refer to pyridine-N-oxide or pyridyl-N-oxide, respectively.

  As used herein, the term "salt" refers to an acid addition salt or base addition salt of a compound of the present invention. "Salt" especially includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and which are typically not biologically or otherwise undesirable. . In many cases, the compounds of the present invention can form acid and / or base salts by the presence of amino and / or carboxyl groups, or groups similar thereto.

  Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, eg acetates, aspartates, benzoates, besylates, bromides / hydrobromides, heavy salts Carbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophyllate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconic acid Salt, glucuronate, hippurate, hydroiodide / iodide salt, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelicate Mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate salt Dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.

  Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.

  Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfone Examples include acids, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

  Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts And magnesium salts are included.

  Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Be Particular organic amines include isopropylamine, benzathine, coriolate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

  The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic site by conventional chemical methods. Generally, such salts are prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.) Or by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable when practical. Further lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth. (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabelled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure illustrated by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number . Examples of isotopes that can be incorporated into the compounds of the present invention include ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, respectively. And isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ^.sup.125I . The present invention contemplates that various isotopically-labeled compounds as defined herein, for example, therein exist radioactive isotopes such as ³ H and ¹⁴ C, or non-radioactive isotopes such as ² H and ¹³ C. Including things. Such isotopically labeled compounds can be used for metabolism studies (by ¹⁴ C), response rate studies (eg by ² H or ³ H), positron emission tomography (PET) or single, including drug or substrate tissue distribution assays. It is useful in detection or imaging techniques such as single photon emission computed tomography (SPECT) or in radiation treatment of patients. In particular, ¹⁸ F or labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the formula (I) are generally attached examples and preparations using conventional isotope labeling reagents by conventional techniques known to the person skilled in the art or in place of previously used unlabeled reagents. It can be prepared by methods analogous to those described in

Furthermore, substitution with heavier isotopes, in particular deuterium (ie ² H or D), results in greater metabolic stability, eg, increased in vivo half-life, or decreased required dose, or improved in therapeutic index. It may bring about certain therapeutic benefits. It is understood that deuterium in this context is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, specifically deuterium, can be defined by the enrichment factor of the isotope. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of the designated isotope. Where the substituent in the compound of the present invention means deuterium, such compound is at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000, for each designated deuterium atom (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90 % Deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (deuterium incorporation) With an isotopic enrichment factor of 99.5%).

Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may, those substituted by isotopes _(e.g., D 2 _O, d 6 _- acetone, d _6-DMSO) includes.

  Compounds of the invention, ie compounds of the formula (I) containing a group capable of acting as a donor and / or acceptor for hydrogen bonding, form a co-crystal with a suitable co-crystal former There is something I can do. These co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedure comprises contacting, in crystallization, heating, co-sublimation, eutectic or in solution together with a co-crystal former under crystallization conditions, and thereby formed Isolating the co-crystals. Suitable co-crystal formers include those described in WO 2004/078163. Thus, the invention further provides a co-crystal comprising a compound of formula (I).

  As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives, which would be known to the person skilled in the art. Agents (eg, antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, additives, disintegrants, lubricants, sweetening agents, flavoring agents, coloring agents And the like, as well as combinations thereof (see, eg, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

  The term "therapeutically effective amount" of a compound of the invention causes a biological or medical response (e.g., reduction or inhibition of enzyme or protein activity) of a subject or ameliorates the condition, alleviates a condition, a disease Refers to the amount of a compound of the invention, such as delaying or delaying the progression of, or preventing disease. In one non-limiting embodiment, the term "therapeutically effective amount" is (1) (i) mediated by MALT1, or (ii) related to MALT1 activity, or (iii) when administered to a subject ) At least partial alleviation, inhibition, prevention and / or amelioration of a condition or disorder or disease characterized by activity (normal or abnormal) of MALT1, or (2) reduction or inhibition of MALT1 activity, or (3) This refers to an amount of a compound of the present invention that is effective for reducing or inhibiting the expression of MALT1, or (4) altering the protein level of MALT1. In another non-limiting embodiment, the term "therapeutically effective amount" is at least partially reduced or inhibited the activity of MALT1 when administered to a cell, or tissue, or non-cellular biological material, or vehicle, Alternatively, it refers to an amount of a compound of the present invention effective for partial or complete reduction or inhibition of MALT1 expression.

  As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In a particular embodiment, the subject is a primate. In yet another embodiment, the subject is a human.

  As used herein, the terms "inhibit", "inhibition" or "inhibiting" reduce or suppress a given condition, symptom or disorder or disease, Alternatively, it refers to a marked reduction in baseline activity of the biological activity or process.

  As used herein, the terms “treat”, “treating” or “treatment” of any disease or disorder, in one embodiment, is a disease or It refers to ameliorating the disorder (ie, delaying, arresting or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating" or "treatment" refers to the alleviation or amelioration of at least one physical parameter, including ones that can not be recognized by the patient. In yet another embodiment, “treat”, “treating” or “treatment” physically (eg, stabilization of a recognizable symptom) or physiologically (eg, the body) of a disease or disorder. Stabilization of parameters), or both of them. In yet another embodiment, "treat", "treating" or "treatment" refers to the prevention or delay of the onset or development or progression of the disease or disorder.

  As used herein, a subject "requires" treatment if the subject benefits from such treatment, biologically, medically, or in quality of life.

  As used herein, the terms "a", "an", "the" as used in the context of the present invention (especially in the context of the claims) Terms and similar terms should be construed as covering both the singular and the plural unless the context clearly indicates otherwise herein or unless the context is explicitly contradictory.

  All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise specifically contradictory to the context. The use of any and all examples or illustrative phrases (eg, "such as") presented herein is intended to be merely illustrative of the invention, unless stated otherwise. There is no limitation on the scope of the present invention.

  Any asymmetric atom (eg, carbon, etc.) of the compounds of the present invention is enriched in racemates or enantiomers, eg, present in (R)-, (S)-or (R, S) -configuration be able to. In certain embodiments, each asymmetric atom is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% mirror image in the (R)-or (S) -configuration. It has an isomer excess, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99%. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)-or trans- (E) -form.

  Thus, as used herein, the compounds of the present invention may be, for example, substantially pure, in the form of one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof It may be present as geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

  Pure or substantially pure geometric or optical isomers, diastereomers of any mixtures of isomers obtained, for example by chromatography and / or fractional crystallization, on the basis of physicochemical differences of the constituents. It can be separated into mer and racemate.

  Separation of diastereomeric salts thereof and optically active acidic compounds, wherein any of the obtained final products or racemates of intermediates is obtained by a known method, for example, using an optically active acid or base Alternatively, they can be resolved into enantiomers by liberation of basic compounds. Thus, in particular, the basic moiety is, for example, an optically active acid such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O, O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid Can be used to resolve the compounds of the present invention into their optical enantiomers by fractional crystallization of the salt formed therewith. Racemic products can also be resolved by chiral chromatography, eg high performance liquid chromatography (HPLC) using a chiral adsorbent.

  In addition, the compounds of the invention can also be obtained in their hydrate form, including their salts, or include other solvents used for their crystallization. The compounds of the present invention may form solvates with pharmaceutically acceptable solvents (including water), essentially or by design, thus the present invention provides solvated and unsolvated forms It is intended to encompass both. The term "solvate" refers to a molecular complex of a compound of the invention (including its pharmaceutically acceptable salts) and one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical art and are known to be innocuous to the recipient (eg, water, ethanol, etc.). The term "hydrate" refers to a complex where the solvent molecule is water.

  The compounds of the present invention, including their salts, hydrates and solvates, can form polymorphs inherently or intentionally.

  In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral and rectal administration. Furthermore, the pharmaceutical composition of the present invention may be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders or suppositories), or in liquid form (without limitation, solutions, suspensions) Agents or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations such as sterilization and / or conventional inert excipients, lubricants or buffering agents, as well as preservatives, stabilizers, wetting agents Adjuvants such as agents, emulsifiers and buffers can be included.

Typically, the pharmaceutical composition is
a) Excipients such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine,
b) for tablets further lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol,
c) If necessary, binders such as, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone,
d) tablets or active ingredients together with disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) absorbents, coloring agents, flavoring agents and sweeteners It is a gelatin capsule.

  The tablets may be either film coated or enteric coated according to methods known in the art.

  Compositions suitable for oral administration comprise an effective amount of a compound of the invention in tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Included in the form of an elixir. Compositions intended for oral use are prepared according to any method known in the art for producing pharmaceutical compositions, and such compositions provide a pharmaceutically elegant and palatable preparation It may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These additives are, for example, inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating agents and disintegrants such as corn starch or alginic acid, binders such as starch, gelatin Or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may be as hard gelatine capsules wherein the active ingredient is mixed with inert solid excipients such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient may be a water or oily medium such as peanuts It may be provided as a soft gelatin capsule mixed with oil, liquid paraffin or olive oil.

  Particular injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, the composition may also contain other therapeutically valuable substances. The compositions are each prepared according to conventional mixing, granulating or coating methods and contain about 0.1 to 75%, or about 1 to 50% of the active ingredient.

  Suitable compositions for transdermal application contain an effective amount of a compound of the invention together with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage of the skin of the host. For example, a transdermal device may be a backing member, a reservoir containing the compound optionally with a carrier, a rate controlling barrier for delivering the compound of the host's skin at a predetermined rate which is optionally controlled over time. And in the form of a strap including means for securing the device to the skin.

  For example, compositions suitable for topical application to the skin and eye include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations for delivery, such as by aerosol. Such topical delivery systems are particularly suited for prophylactic use in skin applications such as the treatment of skin cancer such as sunscreen creams, lotions, sprays and the like. Thus, topical delivery systems are particularly suitable for use in topical formulations, including cosmetic formulations that are well known in the art. These may include solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

  As used herein, topical application may also relate to inhalation or intranasal application. They are conveniently in the form of dry powder inhalers (dry alone, as a mixture, either as a mixture, eg as a dry blend with lactose, or as mixed component particles with eg phospholipids) or suitable With or without a propellant, it can be delivered in the form provided by an aerosol spray from a pressured container, a pump, a spray, a sprayer or a nebulizer.

  The invention further provides anhydrous pharmaceutical compositions and dosage forms comprising a compound of the invention as an active ingredient, since water can facilitate the degradation of certain compounds.

  Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Thus, anhydrous compositions are packaged such that the compositions can be included in a suitable formulation kit using materials known to prevent exposure to water. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

  The invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compounds of the invention as the active ingredient degrade. Such agents are referred to herein as "stabilizers" and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers, and the like.

Synthesis of Compounds of the Invention The synthesis of compounds of the invention is carried out as outlined in Scheme 1:

  Treatment of the activated acid, for example activated as imidazolide, with malonic acid monoester dianions gives β-ketoester 2 after workup. Condensation with an equivalent solvent such as dimethylformamide-dimethylacetal or triethyl orthoformate at elevated temperature in an organic solvent such as ethanol, followed by cyclocondensation with aminopyrazole gives substituted pyrazolo-pyrimidines 3. If a chiral acid is used in step 1, partial racemization may occur during the reaction sequence, depending on the substitution pattern. In this case, the final product can be purified to high enantiomeric purity by chiral chromatography, typically as shown for Example 119.

  Deprotection of the ester gives the acid 4. Curtius rearrangement of acid 4 provides an intermediate isocyanate which can be reacted with the appropriate aniline or aminopyridine to form the final product in a one pot reaction.

  The synthesis of aminopyrazoles such as 3-amino-5-chloropyrazole can be carried out as follows (Scheme 2):

  Treatment of the aminopyrazole under Sandmeyer conditions gives 3-chloropyrazole. Nitration gives N-nitropyrazole, which on heating, rearranges to the desired 3-chloro-5-nitropyrazole. Reduction of the nitro group using iron, tin or tin chloride finally gives the desired 3-amino-5-chloropyrazole 10.

  The anilines and aminopyridines used in the present invention can be prepared using the following route:

  Treatment of substituted para-nitro-chlorobenzene or p-nitrochloropyridine with a nucleophile in an inert solvent such as DMF provides substituted product 12. In this case, the nucleophile can be an anion of a deprotonated alcohol, an amine, a lactam or a heterocycle such as 1,2,3 triazole. Finally, reduction of the nitro substituent using tin or iron in an acidic medium gives the desired aminophenyl- or aminopyridyl-derivative 13.

  Alternatively, aniline or aminopyridine can be prepared by Curtius rearrangement of the appropriate aryl acid (Scheme 4):

  Treatment of acid 14 with diphenylphosphoryl azide and base in t-butanol affords t-butoxy-carbonyl protected amino compound 15, which is deprotected under acidic conditions using HCl or TFA to afford the desired aniline / Aminopyridine 16 can be obtained. Certain aminopyridines and anilines can be prepared by palladium catalyzed coupling of aryl halides with boronic acids according to Scheme 5:

  The pyridones of the present invention are generally prepared by alkylation of hydroxypyridines (Scheme 6):

  Treatment of hydroxypyridine 19 with a base such as potassium carbonate and alkyl halide leads to the formation of pyridone 20 and alkoxypyridine 22. Depending on the substitution pattern of the reactants, selectivity towards one or the other reaction product can be achieved. After separation of the product, the compounds can each be reduced using standard iron or tin mediated reduction reactions to obtain aminopyridone 21 and amino-alkoxypyridine 23.

Experimental term abbreviation Ac ₂ O acetic anhydride AcOEt ethyl acetate AcOH acetic acid Boc ₂ O di-tert-butyl dicarbonate bs broad singlet BuLi n-butyl lithium CaCl ₂ calcium chloride CCl ₄ carbon tetrachloride CDI carbonyldiimidazole CHCl ₃ chloroform CH ₃ CN Acetonitrile CO ₂ Carbon Dioxide Cs ₂ CO ₃ Cesium Carbonate d Doublet DAST Diethylamino Sulfur Difluoride Difluorosulfur DCE 1,2-Dichloroethane DCM Dichloromethane DMF Dimethylformamide DMSO Dimethylsulfoxide DPPA Diphenylphosphoryl Azide Et ₂ O Diethyl Ether Et ₃ N Triethylamine EtOH Ethanol Ethanol h Time HCl hydrochloric acid hept. Heptet H ₂ O water H ₂ SO ₄ sulfuric acid HCHO formaldehyde HCOOH formic acid HNO ₃ nitric acid HPLC high performance liquid chromatography HV high vacuum iPrOH isopropanol IST International Sorbent Technology (supplier)
K ₂ CO ₃ potassium carbonate KNO ₃ potassium nitrate KOH potassium hydroxide LDA lithium diisopropylamide LiAlH ₄ lithium aluminum hydride LiCl lithium chloride lithium hydroxide lithium hydroxide mCPBA meta-chloroperoxybenzoic acid MeI methyl iodide MeOH methanol MnO ₂ manganese dioxide m multiplet M molar concentration min min N normal NaBH ₄ sodium borohydride NaBH (OAc) ₃ triacetoxyborohydride sodium Na ₂ CO ₃ sodium carbonate Na ₂ SO ₄ sodium sulfate sodium sulfate sodium hydride NaHCO ₃ sodium bicarbonate sodium bicarbonate NaIO ₄ periodic acid sodium NaOH sodium hydroxide _NH 4 Cl ammonium chloride NMR nuclear magnetic resonance Pd / C charcoal palladium on carbon PdCl ₂ ( Ph _{3) 2} Bis (triphenylphosphine) palladium dichloride (II)
Pd _{2 (dba) 3} tris (dibenzylideneacetone) dipalladium (0)
Pd (PPh ₃ ) ₄ tetrakis (triphenylphosphine) palladium (0)
pTsOH para-toluenesulfonic acid q quartet RT room temperature Rt holding time singlet SFC supercritical fluid chromatography t triplet TBME tert-butyl methyl ether tBuOH tert-butanol TBAF tetrabutylammonium fluoride TFA THF trifluoroacetic acid THF tetrahydrofuran UPLC ultra high performance liquid chromatography XantPhos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene

Analytical method UPLC method Method B1: Fast 4: Waters UPLC; column: Acquity HSS T3 1.8 μm, 2.1 ^* 50 mm, 60 ° C., eluent A: H ₂ O + 0.05% HCOOH + 3.75 mM ammonium acetate, B: CH ₃ CN + 0.04% HCOOH, gradient: 10 to 95% B in 1.5 minutes, flow rate: 1 ml / min.
Method B2: Method LCMS_2_MIN_FINAL_ANALYSIS: Waters UPLC; Column: Acquity HSS T3, 1.8 μm, 2.1 ^* 50 mm, 60 ° C., Eluent A: H ₂ O + 0.05% HCOOH + 3.75 mM ammonium acetate, B: CH ₃ CN + 0 .04% HCOOH, gradient: 5% to 98% B in 1.4 minutes, flow rate: 1 ml / min.
Method B3: Method LCMS_2_MIN_MONITORING: Waters UPLC; Column: Ascentis Expresse C18 2.1 × 30 mm, 2.7 μm, 60 ° C., eluent A: H ₂ O + 0.05% TFA, B: CH ₃ CN + 0.04% TFA, Concentration gradient: 2% to 98% B in 1.4 minutes, flow rate: 1 ml / min.
Method B4: Method LCMS_SHORT: Waters UPLC; Column: Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm, at 35 ° C., eluent A: H ₂ O + 0.1% TFA, B: CH ₃ CN + 0.1% TFA, gradient: 5% to 100% B in 1.5 minutes, flow rate: 0.6 ml / min.
Method B5: Method LCMS_2_MIN_POLAR: Waters UPLC; Column: Acquity HSS T3, 1.8 μm, 2.1 ^* 50 mm, at 50 ° C. Eluent A: H ₂ O + 0.05% HCOOH + 3.75 mM ammonium acetate, B: CH ₃ CN + 0 .04% HCOOH, gradient: 2% to 98% B in 1.4 minutes, flow rate: 1.2 ml / min.
Method B6: Method LCMS_SPECTRA: Waters UPLC; Column: Acquity HSS T3, 1.8 μm, 2.1 ^* 50 mm, 50 ° C., Eluent A: H ₂ O + 0.05% HCOOH + 3.75 mM ammonium acetate, B: CH ₃ CN + 0 .04% HCOOH, gradient: 5% to 98% B in 1.4 minutes, flow rate: 1.2 ml / min.
Method B7: Method LCMS_10_MIN: Waters UPLC Acquity; Column: Acquity HSS T3, 1.8 μm, 2.1 ^* 50 mm, at 60 ° C., Eluent A: H ₂ O + 0.05% HCOOH + 3.75 mM ammonium acetate, B: CH ₃ CN + 0.04% HCOOH, gradient: 5% to 98% B in 9.4 minutes, flow rate: 1 ml / min.

HPLC Method Method C1: HPLC Acid QC: Waters X-Bridge C18, 2.5 μm, 3 ^* 50 mm, 40 ° C., eluent A: H ₂ O + 0.1% TFA; B: CH ₃ CN + 0.1% TFA. 10 to 98% B in 1.4 minutes, 1.4 minutes hold, flow rate: 1.4 ml / min.
Method C2: Fast acid: Waters X-Bridge C18, 2.5 μm, 3 ^* 30 mm, 40 ° C., eluent A: water + 0.1% TFA; B: CH ₃ CN + 0.1% TFA. 10 to 98% B at a concentration gradient of 3 minutes, hold for 0.5 minutes, flow rate: 1.4 ml / min.

GC / MS Method D1: Gaschromatograph Finnigan Focus GC (Thermo Electron Corporation) Single Quadrupole Mass Analyzer, EI, column Zebron ZB-5 ms, 15 mm, 0.25 mm i. D. , 0.25 μm film thickness, 5% polysularylene, 95% polydimethylsiloxane.

Preparatory method Method A1: HPLC, Waters Sunfire C18 OBD, 5 μm, 30 ^* 100 mm, eluent A: H ₂ O + 0.1% TFA, B: CH ₃ CN + 0.1% TFA.
Method A2: HPLC, Waters X-Bridge C18 OBD, 5 μm, 30 ^* 100 mm, eluent A: H ₂ O + 7.3 mM NH ₄ OH, B: CH ₃ CN + 7.3 mM NH ₄ OH.
Method A3: Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40 ^* 250 mm, eluent A: H ₂ O + 0.1% TFA, B: CH ₃ CN + 0.1% TFA.
Method A4: HPLC, Waters X-Bridge C18 OBD, 10 μm, 19 ^* 150 mm, eluent A: H ₂ O, B: CH ₃ CN.
Method A5: Thar SFC 200, eluting with CO ₂ / MeOH using one of the following columns:
-Princenton PPU 250 × 30 mm, 100 Å, 5 μm,
-Princenton 4-EP 250 × 30 mm, 60 Å, 5 μm,
Reprosil di NH ₂ 250 × 30 mm, 100 Å, 5 μm,
-Princenton Silica 250 × 30 mm, 60 Å, 5 μm,
Waters Atlantis Hilic Silica 250 × 30 mm, 5 μm.

Part A: Synthesis of aminopyrazole A1: 5-chloro-1H-pyrazole-3-amine

a) 5-Chloro-1H-pyrazole 1H-pyrazol-5-amine (23.6 g, 284 mmol) in CH ₃ CN (1 L) at 0 ° C. under nitrogen atmosphere HCl (140 ml, 1420 mmol, 32%) and Copper chloride (56.3 g, 568 mmol) was added. Isopentyl nitrite (80 ml, 568 mmol) was added at 0 ° C. and the mixture was stirred at 0 ° C. for 2 days. Isopentyl nitrite (20 ml, 0.5 eq) was added and the mixture was stirred at room temperature for a further 5.5 days. The reaction mixture was poured slowly into ammonium hydroxide (1 L, 25%) and extracted with AcOEt. The organic phase is separated and the aqueous phase is extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (hexane / TBME 1: 0 to 4: 6) to give 5-chloro-1H-pyrazole. M / z = 103/105 [M + H] +, Rt = 0.48 min (UPLC method B2), ¹ H NMR (600 MHz, DMSO-d ₆ ): δ ppm: 13.00 (bs, 1 H), 7.79 (t , 1H), 6.29 (t, 1H), isoamyl alcohol: 4.28 (t, 1H), 3.41 (q, 2H), 1.30 (q, 2H), 0.85 (d, 6H).

b) 5-Chloro-1-nitro-1H-pyrazole A solution of 5-chloro-1H-pyrazole (3.88 g, 35.2 mmol) in AcOH (5.10 ml, 89 mmol) at 90 ° C. in 90% aqueous HNO ₃ solution (5.10 ml, 35.2 mmol) was added dropwise and the reaction mixture was stirred at 0 ° C. for 2 hours. Then Ac ₂ O (12.92 ml, 137 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours. The mixture was poured into ice water and AcOEt and Na ₂ CO ₃ (33.6 g, 317 mmol) were added. The organic phase is separated and the aqueous phase is extracted with AcOEt. The combined organic layers were washed with saturated aqueous NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ and concentrated to give 5-chloro-1-nitro-1H-pyrazole. M / z = 146/148 [M-H]-, Rt = 0.71 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm: 8.91 (d, 1 H), 6.90 (d, 1H).

c) 5-Chloro-3-nitro-1H-pyrazole Dissolve 5-chloro-1-nitro-1H-pyrazole (5.44 g, 35.0 mmol) in dry anisole (70 ml) in an autoclave and seal the reactor did. The mixture was heated at 140 ° C. for 16 hours. The mixture was cooled, filtered and the filtrate was evaporated to dryness. To the residue was added hexane and the suspension sonicated and triturated. The precipitate was filtered and rinsed with hexane to give 5-chloro-3-nitro-1H-pyrazole. M / z = 146/148 [ M-H] -, Rt = 0.60 min (UPLC method ^{B2), 1 H NMR (400} MHz, DMSO-d 6): δ ppm: 7.29 (s, 1H).

d) 5-Chloro-1H-pyrazol-3-amine A solution of 5-chloro-3-nitro-1H-pyrazole (4.345 g, 29.2 mmol) in MeOH (389 ml) at room temperature with 32% aqueous HCl (57 .3 ml, 583 mmol) were carefully added. After cooling to 0 ° C., SnCl ₂ (27.6 g, 146 mmol) was added in small portions and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness, the residue was diluted with ethyl acetate and 30% aqueous NaOH solution was added until the pH was basic. After cooling to 0 ° C. overnight, the salt was filtered off through a pad of celite and the cake was rinsed with AcOEt and water. The organic phase is separated and the aqueous phase is extracted with AcOEt. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give 5-chloro-1H-pyrazole-3-amine. M / z = 118/120 [M + H] +, Rt = 0.36 minutes (UPLC method B2), ¹ H NMR (600 MHz, DMSO-d ₆ ): δ ppm: 11.54 (s, 1 H), 5.25 (s , 2H), 5.20 (s, 1 H).

Part B: Synthesis of carboxylic acid compounds B1: (R) -2-methoxy-3-methylbutanoic acid

a) (R) -Benzyl 2-hydroxy-3-methylbutanoate To benzyl bromide (6.00 ml, 50.8 mmol) in D-.alpha.-hydroxyisovaleric acid (5 g, 42.3 mmol) in DMF (50 ml) ) And DBU (6.38 ml, 42.3 mmol) were added and the reaction mixture was stirred at room temperature for 64 hours. The solvent was evaporated and the residue was dissolved in AcOEt / water. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 9/1) to give (R) -benzyl 2-hydroxy-3-methylbutanoate. M / z = 209 [M + H] +, Rt = 0.95 minutes (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.46-7.29 (m, 5H), 5.35 (d, 1H), 5.14 (d, 2H), 3.87 (dd, 1H), 2.00-1.90 (m, 1H), 0.88 (d, 3H), 0.82 (d, 3H).

b) (R) -Benzyl 2-methoxy-3-methylbutanoate (R) -benzyl 2-hydroxy-3-methylbutanoate (7.8 g, 37.5 mmol) in THF (150 ml),- At 20 ° C. NaH (1.80 g, 44.9 mmol, 60% oil dispersion) was added and the mixture was allowed to warm to room temperature over 30 minutes. After cooling to 0 ° C., dimethyl sulfate (4.26 ml, 44.9 mmol) was added and the reaction mixture was stirred at room temperature for 117 hours. The mixture was quenched with Et ₃ N, acidified with 1 N HCl, the aqueous phase extracted with TBME, the organic phase washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 9/1) to give (R) -benzyl 2-methoxy-3-methylbutanoate. M / z = 223 [M + H] +, Rt = 1.15 minutes (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.30 (m, 5H), 5.26-5.10 (m, 2H), 3.63 (d, 1 H), 3.27 (s, 3 H), 2.05-1.90 (m, 1 H), 0.88 (d, 3 H), 0.84 (d, 3 H).

c) (R) -2-methoxy-3-methylbutanoic acid (R) -benzyl 2-methoxy-3-methylbutanoate (3.4 g, 15.30 mmol) in AcOEt (100 ml) to Pd / C (3.4 g, 15.30 mmol) 0.81 g, 10% Pd) was added. The mixture was purged with H ₂ gas and the suspension was stirred at room temperature for 3 hours. The reaction mixture was filtered, washed with AcOEt and the solvent was evaporated to give (R) -2-methoxy-3-methylbutanoic acid. M / z = 133 [M + H] +, Rt = 0.54 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.63 (s, 1 H), 3.45 (d, 1 H) , 3.27 (s, 3 H), 2.00-1. 90 (m, 1 H), 0.91 (d, 3 H), 0.87 (d, 3 H).
B2: (S) -2-methoxy-3-methylbutanoic acid

(S) -2-Methoxy-3-methylbutanoic acid was similarly prepared as described in Procedure B1, using L-α-hydroxyisovaleric acid instead of D-α-hydroxyisovaleric acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.6 (s, 1 H), 3.46 (d, 1 H), 3. 27 (s, 3 H), 1. 95 (dt d, 1 H), 0.91 (d, 3 H), 0.87 (d, 3H).
B3: (S) -2- (2-methoxyethoxy) propanoic acid

To a suspension of NaH (3.19 g, 80 mmol, 60% oil dispersion) in DMF (60 ml) at 0 ° C. was added 2-methoxyethanol (2.75 ml, 34.8 mmol). After 30 minutes (R) -2-bromopropanoic acid (1.5 ml, 16.6 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water, concentrated and extracted with AcOEt. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give (S) -2- (2-methoxyethoxy) propanoic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.56 (bs, 1 H), 3.92 (q, 1 H), 3.66-3.57 (m, 1 H), 3.50 to 3.40 (m, 4 H), 3.24 (s) , 3H), 1.26 (d, 3H).

  Similarly, the following acids were prepared:

B11: 2,3-dimethoxypropanoic acid

a) Methyl 2,3-dihydroxypropanoate Methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (3 ml, 20.7 mmol) and 1 N HCl (25.9 ml, 25.9 mmol) in MeOH The solution in 40 ml) was stirred at room temperature for 20 hours. The reaction mixture is extracted with AcOEt, the aqueous phase is extracted with 2-methyltetrahydrofuran, the combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated to give methyl 2,3-dihydroxypropanoate The ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 5.38 (d, 1 H), 4.82 (t, 1 H), 4.08-4.03 (m, 1 H), 3.62 (s, 3 H), 3.57-3. 52 (m , 2H).

b) Methyl 2,3-dimethoxypropanoate methyl 2,3-dihydroxypropanoate (500 mg, 4.16 mmol), methyl iodide (5.21 ml, 83 mmol) and silver oxide (9.65 g, 41.6 mmol) A solution of 1 in DCM (10 ml) was stirred at room temperature overnight. Water was added and the mixture was extracted with AcOEt, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 0/1) to give methyl 2,3-dimethoxypropanoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.02 (dd, 1 H), 3.67 (d, 3 H), 3.60-3.51 (m, 2 H), 3.30 (s, 3 H), 3.24 (s, 3 H) ).

c) To a solution of methyl 2,3-dimethoxypropanoate (190 mg, 1.28 mmol) in THF (3 ml) was added NaOH (0.96 ml, 1.92 mmol). The reaction mixture was stirred at room temperature overnight. The pH was adjusted to 2-3 by addition of 1 N HCl. The mixture was extracted with AcOEt, dried over Na ₂ SO ₄ , filtered and concentrated to give 2,3-dimethoxypropanoic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.74 (bs, 1 H), 3.89 (dd, 1 H), 3.58-3.50 (m, 2 H), 3.29 (s, 3 H), 3.24 (s, 3 H) ).
B12: 2,4-dimethoxybutanoic acid

a) 3-Methoxydihydrofuran-2 (3H) -one α-hydroxy-butyrolactone (1.33 g, 13.03 mmol), methyl iodide (8.15 ml, 130 mmol) and silver oxide (9.7 g, 41.9 mmol) A solution of) in dry CHCl ₃ (43.4 ml) was stirred at 63 ° C. for 3 hours without light. The reaction mixture was cooled, filtered over a pad of celite and the filtrate was concentrated to give 3-methoxydihydrofuran-2 (3H) -one. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.31 (tdd, 1H), 4.24-4.14 (m, 2H), 3.41 (d, 3H), 2.55-2.45 (m, 1H), 2.12-2.01 (m, 1H).

b) 2,4-Dimethoxybutanoic acid H ₂ SO ₄ (0.022 ml, 0.413 mmol), 3-methoxydihydrofuran-2 (3H) -one (1.6 g, 13.78 mmol) and trimethyl orthoformate ( To a stirred solution of 2.92 g, 27.6 mmol) in MeOH (10 ml) was added. The mixture was stirred at 50 ° C. overnight. After cooling to room temperature, the reaction mixture was evaporated. The residue was dissolved in THF (28.3 ml), 2M aqueous LiOH solution (8.50 ml, 17.0 mmol) was added and the reaction mixture was stirred at room temperature for 48 hours. Water and AcOEt were added. The separated aqueous phase was acidified with 1 N HCl to pH = 1, extracted with AcOEt, the organic phase was dried on a phase separation cartridge (IST) and evaporated to give 2,4-dimethoxybutanoic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.74 (dd, 1H), 3.45-3.30 (m, 2H), 3.25 (s, 3H), 3.21 (s, 3H), 1.94-1.83 (m , 1H), 1.81-1.69 (m, 1H).
B13: 5-methyltetrahydrofuran-2-carboxylic acid

To 5-methyl-2-furoic acid (2.15 g, 16.54 mmol) in AcOEt (150 ml) was added Pd / C (0.880 g). The suspension was stirred at room temperature under H ₂ atmosphere for 4 hours. The reaction mixture was filtered, washed with AcOEt, and the filtrate was evaporated to give 5-methyltetrahydrofuran-2-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.50 (s, 1 H), 4.26 (dd, 1 H), 4.01 (dp, 1 H), 2.19-2.11 (m, 1 H), 2.02-1.91 (m , 2H), 1.46-1.35 (m, 1 H), 1.20 (d, 3 H).
B14: 2-methoxy-2- (tetrahydro-2H-pyran-4-yl) acetic acid

a) 1- (Tetrahydro-2H-pyran-4-yl) prop-2-en-1-ol solution of tetrahydro-2H-pyran-4-carbaldehyde (5.0 g, 43.8 mmol) in THF (146 ml) To the mixture was added dropwise 1N vinylmagnesium bromide (52.6 ml, 52.6 mmol) in THF at -78.degree. The reaction mixture was stirred for 3 hours at -78 ° C., and quenched with saturated aqueous _NH 4 Cl. The mixture was extracted with AcOEt, the organic layer was dried on a phase separation cartridge (IST) and evaporated. The residue is purified by flash chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 1/1) to give 1- (tetrahydro-2H-pyran-4-yl) prop-2-en-1-ol The ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 5.86-5.77 (m, 1H), 5.19-5.03 (m, 2H), 4.75 (d, 1H), 3.90-3.80 (m, 2H), 3.69 (tdt, 1 H), 3.23 (ddd, 2 H), 1.63 (ddq, 1 H), 1.55-1. 42 (m, 2 H), 1.32-1. 21 (m, 2 H).

b) 4- (1-Methoxyallyl) tetrahydro-2H-pyran 1- (tetrahydro-2H-pyran-4-yl) prop-2-en-1-ol (4.93 g 34.) in THF (217 ml). To 7 mmol) NaH (2.77 g, 69.3 mmol) was added over 30 minutes at -78 C and the mixture was stirred for 30 minutes at room temperature. After cooling to 0 ° C., dimethyl sulfate (6.63 ml, 69.3 mmol) was added and the reaction mixture was stirred at room temperature overnight. Et ₃ N (9.66 ml, 69.3 mmol) was added and the mixture was acidified with 4 N HCl and extracted with Et ₂ O. The organic phase was dried on a phase separation cartridge (IST) and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 7/3) to give 4- (1-methoxyallyl) tetrahydro-2H-pyran. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 5.63 (ddd, 1H), 5.33-5.16 (m, 2H), 3.90-3.78 (m, 2H), 3.39-3.21 (m, 3H), 3.17 (s, 3 H), 1.70-1. 57 (m, 2 H), 1. 44 (dt, 1 H), 1. 29-1. 12 (m, 2 H).

c)-4-2-methoxy-2- (tetrahydro -2H- pyran-yl) acetic acid _{CCl 4 (12.8ml), CH 3} CN (12.8ml), water (17.1 ml) solution of 4- (1- methoxy allyl) tetrahydro -2H- pyran (1 g, the _{6.40mmol), NaIO 4 (5.20g,} 24.32mmol) and ruthenium trichloride (0.027 g, 0.13 mmol) was added. The suspension was stirred at room temperature for 2 hours. The solid was removed by filtration, rinsed with CHCl _3, the filtrate was extracted with CHCl _3, dried the organic phase phase separation cartridge (IST), and evaporated. The residue was diluted in DCM, filtered through a pad of celite and evaporated to give 2-methoxy-2- (tetrahydro-2H-pyran-4-yl) acetic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.70 (s, 1 H), 3.88-3.80 (m, 2 H), 3.52 (d, 1 H), 3.28-3.20 (m, 2 H), 3.17 (s , 3H), 1.92-1.82 (m, 1H), 1.41 (dddd, 4H).
B15: 1- (Dimethylamino) cyclopropanecarboxylic acid

To 1-aminocyclopropanecarboxylic acid (5.2 g, 48.9 mmol) was added 37% formaldehyde in H ₂ O (10 ml, 134 mmol) and formic acid (13 ml, 332 mmol) was added dropwise. After stirring for 2 hours at reflux and cooling to room temperature, 37% aqueous HCl (5 ml, 58.6 mmol) was added and the mixture was concentrated. The residue was treated with MeOH (3 ml) and Et ₂ O (20 ml), the suspension filtered and the solid dried in vacuo to give 1- (dimethylamino) cyclopropanecarboxylic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.92 (s, 6 H), 1.70 (t, 2 H), 1. 45 (t, 2 H).
B16: 2- (methoxymethyl) tetrahydrofuran-2-carboxylic acid

a) Ethyl 2- (methoxymethyl) tetrahydrofuran-2-carboxylate Diisopropylamine (5.93 ml, 41.6 mmol) in THF (173 ml) at −78 ° C. in 10 M BuLi in hexane (4.16 ml, 41. 6 mmol) were added dropwise. The solution was stirred at -78 ° C for 2 hours. To this freshly prepared solution of LDA, a solution of (S) -ethyltetrahydrofuran-2-carboxylate (5.0 g, 34.7 mmol) in THF (173 ml) was added dropwise at -78.degree. The reaction mixture was stirred at -78 ° C for 1.5 hours. Chloro (methoxy) methane (2.90 ml, 38.1 mmol) was then added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was quenched with saturated aqueous NH ₄ Cl and extracted twice with AcOEt. The organic layer was dried on a phase separation cartridge (IST) and evaporated. The crude product is purified by flash chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 1/3) to give ethyl 2- (methoxymethyl) tetrahydrofuran-2-carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.08 (m, 2 H), 3.80 (m, 2 H), 3.59 (d, 1 H), 3.40 (d, 1 H), 3.25 (s, 3 H), 1.82 (m, 4H), 1.18 (m, 3H).

b) Ethyl 2- (methoxymethyl) tetrahydrofuran-2-carboxylate Ethyl 2- (methoxymethyl) tetrahydrofuran-2-carboxylate (3.72 g, 19.8 mmol) in THF (49.4 ml) / MeOH (24.7 ml) To a solution in water / water (24.7 ml) was added LiOH monohydrate (0.91 g, 21.7 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was evaporated, the residue was dissolved in AcOEt and acidified with 1 M aqueous HCl. The phases were separated and the aqueous layer was extracted with AcOEt. The combined organic layers were dried on a phase separation cartridge (IST) and evaporated to give 2- (methoxymethyl) tetrahydrofuran-2-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.40 (bs, 1 H), 3.83-3.76 (m, 2 H), 3.58 (d, 1 H), 3.38 (d, 1 H), 3.25 (s, 3 H) ), 1.87-1.76 (m, 4H).
Part C: Synthesis of .beta.-ketoesters C1: (S) -tert-butyl 4-methoxy-3-oxopentanoate

To a solution of (S) -2-methoxypropanoic acid (10.0 g, 96 mmol) in THF (200 ml) was added CDI (17.13 g, 106 mmol) at 0 ° C. and the reaction mixture was stirred at room temperature for 3 hours. To a solution of 3- (tert-butoxy) -3-oxopropanoic acid (22.2 ml, 144 mmol) in THF (200 ml) in a separate flask is added dropwise 2M isopropylmagnesium chloride (139 ml, 279 mmol) in THF at 0 ° C. The reaction mixture was stirred at 20 ° C. for 3 hours. The solution was then added dropwise to the acylimidazole solution at 0 ° C., and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 10% aqueous citric acid (25 ml), extracted with AcOEt, washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 100/0 to 70/30) to give (S) -tert-butyl 4-methoxy-3-oxopentanoate. M / z = 203 [M + H] +, Rt = 0.91 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.85 (q, 1 H), 3.54-3.46 (m, 2H), 3.27 (s, 3H), 1.40 (s, 9H), 1.19 (d, 3H).

  Similarly, the following keto esters were prepared:

C43: (S) -tert-butyl 4-((tert-butoxycarbonyl) (methyl) amino) -3-oxopentanoate

To a solution of Boc-N-Me-L-alanine (5.0 g, 24.6 mmol) in THF (100 ml) is added CDI (4.39 g, 27.1 mmol) at 0 ° C., and the reaction mixture is added at room temperature 3 Stir for hours. In a separate flask, 2M isopropylmagnesium chloride (35.7 ml, 71.3 mmol) in THF, 100 ml of 3- (tert-butoxy) -3-oxopropanoic acid (5.68 ml, 36.9 mmol) in THF at 100C. The solution was added drop wise to the medium solution and the reaction mixture was stirred at room temperature for 3 hours. This solution was then added dropwise to the acylimidazole solution at 0 ° C., and the resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched by the addition of 10% aqueous citric acid (100 ml) and the aqueous layer was extracted twice with AcOEt. The combined organic layers were washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 7/3) and (S) -tert-butyl 4-((tert-butoxycarbonyl) (methyl) amino) -3 An oxopentanoate is obtained. M / z = 302 [M + H] +, Rt = 1.23 minutes (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.41-4.32 and 4.18-4.10 (m, 1H) 3.53 -3.28 (m, 2H), 2.80 and 2.74 (2s, 3H), 1.40 and 1.34 (2s, 18H), 1.24-1. 17 (m, 3H).
C44: (R) -tert-butyl 4-methoxy-5-methyl-3-oxohexanoate

Add a solution of (R) -2-methoxy-3-methylbutanoic acid (2.0 g, 15.1 mmol) in THF (50 ml) at 0 ° C. under argon and add CDI (2.78 g, 16.65 mmol) and react The mixture was stirred at room temperature for 24 hours. In a separate flask, 2 M isopropylmagnesium chloride (25.0 ml, 49.9 mmol) in THF, 50 ml of 3- (tert-butoxy) -3-oxopropanoic acid (3.68 ml, 22.7 mmol) at 0 ° C. The solution was added drop wise to the medium solution and the reaction mixture was stirred at room temperature for 1 hour. This solution was then added dropwise to the acylimidazole solution at 0 ° C., and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of 10% aqueous citric acid (200 ml) and water. The aqueous layer was extracted twice with AcOEt. The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, water and brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 98/2) to give (R) -tert-butyl 4-methoxy-5-methyl-3-oxohexanoate The ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.48 (d, 2 H), 3.43 (d, 1 H), 3.28 (s, 3 H), 2.01-1.96 (m, 1 H), 1.41 (s, 9 H ), 0.88 (d, 3 H), 0.83 (d, 3 H).
C 45: (S) -tert-butyl 3- (3- (tert-butoxy) -3-oxopropanoyl) morpholine-4-carboxylate

a) (S) -4- (tert-butoxycarbonyl) morpholine-3-carboxylic acid (S) -morpholine-3-carboxylic acid (1.0 g, 7.63 mmol) and Boc ₂ O (1.77 ml, 7. 7). A mixture of 63 mmol) in 10% NaHCO ₃ solution in water (10 ml, 7.63 mmol) and 1,4-dioxane (10 ml) was stirred at room temperature for 16 hours. Water and AcOEt were added to the mixture and the phases separated. The aqueous layer was acidified to pH 3-4 with 1 M aqueous citric acid (12 ml) and extracted three times with AcOEt. The organic layer is washed with brine, dried on a phase separation cartridge (IST), the solvent is evaporated, the residue is dried in vacuo and (S) -4- (tert-butoxycarbonyl) morpholine-3-carboxylic acid I got M / z = 232 [M + H] +, Rt = 0.70 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 12.94 (bs, 1 H), 4.32 (dd, 1 H) , 4.15 (dd, 1H), 3.79 (ddd, 1H), 3.58-3.51 (m, 2H), 3.39-2.97 (m, 2H), 1.38 (d, 9H).

b) (S) -4-tert-Butyl 3-methylmorpholine-3,4-dicarboxylate (S) -4- (tert-butoxycarbonyl) morpholine-3-carboxylic acid (1.31 g, 5.66 mmol) To a mixture of MeOH (10 ml) at 0 ° C. was added dropwise 2M trimethylsilyl-diazomethane in hexane (8.0 ml, 16.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Water was added to the mixture and the aqueous layer was extracted twice with AcOEt. The organic layer was washed with saturated aqueous NaHCO ₃ solution, water, brine, dried over a phase separation cartridge (IST) and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 7/3) to give (S) -4-tert-butyl 3-methylmorpholine-3,4-dicarboxylate Obtained. M / z = 246 [M + H] +, Rt = 0.89 min (UPLC method B2).

c) (S) -tert-Butyl 3- (3- (tert-butoxy) -3-oxopropanoyl) morpholine-4-carboxylate tert-butyl acetate (2.32 ml, 17.4) under argon at -78 ° C. A solution of 1 mmol) in dry THF (10 ml) was added dropwise to a mixture of 2 M LDA in THF / heptane / ethylbenzene (7.49 ml, 15.0 mmol) and dry THF (10 ml). After stirring for 1 hour at −78 ° C., a solution of (S) -4-tert-butyl 3-methylmorpholine-3,4-dicarboxylate (1.05 g, 4.28 mmol) in dry THF (10 ml) is reacted Added dropwise to the mixture. The resulting reaction mixture was stirred at -78 ° C for 3 hours. The mixture was poured into 1 M aqueous HCl and extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO ₃ solution, dried on a phase separation cartridge (IST) and the solvent was evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 4/1) and (S) -tert-butyl 3- (3- (tert-butoxy) -3-oxopropanoyl ) Morpholine-4-carboxylate was obtained. M / z = 330 [M + H] +, Rt = 1.11 minutes (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.56 (m, 1 H), 4.33 (m, 1 H) , 3.81-3.50 (m, 5H), 3.38-3.34 (m, 1H), 2.99 (m, 1H), 1.41-1.34 (m, 18H).
C46: (4S, 5R) -tert-butyl 4, 5-dimethoxy-3-oxohexanoate

a) (2S, 3R) -2,3-Dihydroxybutanoic acid L-Threonine (2.2 g, 18.5 mmol) in 0.5 M H ₂ SO ₄ aqueous solution (40 ml, 20 mmol) at 0 ° C. in nitrous acid A solution of sodium (4.14 g, 60 mmol) in water (15 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated, the residue dissolved in EtOH, filtered and the filtrate concentrated. The residue was dissolved in water, frozen and lyophilized to give (2S, 3R) -2,3-dihydroxybutanoic acid. ¹ H NMR (400 MHz, D ₂ O) δ ppm: 4.01 (m, 1 H), 3.79 (m, 1 H), 1.20 (d, 3 H).

b) (2S, 3R) -Methyl 2,3-dihydroxybutanoate (2S, 3R) -2,3-dihydroxybutanoic acid (1.90 g, 15.8 mmol) in a mixture of MeOH (35 ml) at 0 ° C. SOCl ₂ (2.89 ml, 39.5 mmol) was added dropwise at. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 1/1) to give (2S, 3R) -methyl 2,3-dihydroxybutanoate . M / z = 135 [M + H] +, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 4.09 (m, 1 H), 4.03 (m, 1 H), 3.83 (s, 3 H), 1.31 (d, 3 H) .

c) (2S, 3R) -Methyl 2,3-dimethoxybutanoate (2S, 3R) -Methyl 2,3-dihydroxybutanoate (1.70 g, 12.7 mmol), methyl iodide (15.85 ml, A solution of 253 mmol) and silver oxide (17.6 g, 76 mmol) in DCM (100 ml) was stirred at room temperature in the dark for 6 days. The mixture is filtered, concentrated and the crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 1/1) to give (2S, 3R) -methyl 2,3-dimethoxybutano I got ae. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.85 (m, 1 H), 3.66 (s, 3 H), 3.61 (m, 1 H), 3.29 (s, 3 H), 3.21 (s, 3 H), 1.07 (d, 3H).

d) (4S, 5R) -tert-butyl 4,5-dimethoxy-3-oxohexanoate at -78 ° C in tert-butyl acetate (0.33 ml, 2.47 mmol) in dry THF (0.9 ml) The solution was added dropwise to a mixture of dry THF (0.9 ml) and 2 M LDA in THF / heptane / ethylbenzene (1.08 ml, 2.16 mmol). After stirring for 1 hour at −78 ° C., the solution was added dropwise via a solution of (2S, 3R) -methyl 2,3-dimethoxybutanoate (100 mg, 0.62 mmol) in dry THF (0.9 ml) . The resulting mixture was stirred at -78 ° C for 2 hours. The reaction mixture was poured into 1 M aqueous HCl solution, extracted with AcOEt, dried on a phase separation cartridge (IST) and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 9/1) to give (4S, 5R) -tert-butyl 4,5-dimethoxy-3-oxohexanoate The M / z = 247 [M + H] +, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.78 (m, 1 H), 3.64 (m, 1 H), 3.48 (s, 2 H), 3.21 (s, 3H), 1.40 (s, 9H), 1.06 (d, 3H), 1 CH3 is unclear due to water.
C47: (S) -tert-butyl 4-((tert-butoxycarbonyl) (methyl) amino) -5-methyl-3-oxohexanoate

a) (S) -Methyl 2-((tert-butoxycarbonyl) (methyl) amino) -3-methylbutanoate N-Me-Boc-Val-OH (2.0 g, 8.65 mmol) in MeOH (29 ml) To the mixture in) was added dropwise at 0 ° C. 2 M trimethylsilyldiazomethane in hexane (8.65 ml, 17.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the mixture and the aqueous layer was extracted twice with AcOEt. The organic layer was washed with saturated aqueous NaHCO ₃ solution, water, brine, dried over a phase separation cartridge (IST) and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 4/1) to give (S) -methyl 2-((tert-butoxycarbonyl) (methyl) amino) -3-methyl Butanoate was obtained. M / z = 246 [M + H] +, Rt = 1.15 minutes (UPLC method B2).

b) (S) -tert-Butyl 4-((tert-butoxycarbonyl) (methyl) amino) -5-methyl-3-oxohexanoate tert-butyl acetate (2.20 ml, at -78 ° C. under argon) A solution of 16.3 mmol) in dry THF (10 ml) was added dropwise to a mixture of 2 M LDA in THF / heptane / ethylbenzene (7.13 ml, 14.3 mmol) and dry THF (10 ml). After stirring for 1 hour at −78 ° C., dry THF (10 g) of (S) -methyl 2-((tert-butoxycarbonyl) (methyl) amino) -3-methylbutanoate (1.0 g, 4.1 mmol) ) Solution was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at -78 ° C for 2 hours. The mixture was poured into 1 M aqueous HCl and extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO ₃ solution, dried on a phase separation cartridge (IST) and the solvent was evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 9/1) to give (S) -tert-butyl 4-((tert-butoxycarbonyl) (methyl) amino)- 5-methyl-3-oxohexanoate was obtained. M / z = 330 [M + H] +, Rt = 1.34 minutes (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 4.29-3.95 (d, 1 H), 3.52-3.37 ( m, 2H), 2.68 + 2.61 (s, 3H), 2.14 (m, 1H), 1.42-1.39 (m, 18H), 0.87 (dd, 3H), 0.77 (dd, 3H).
Part D: Synthesis of C-substituted pyrazolo [1,5-a] pyrimidine-6-carboxylate D1: (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine -6-carboxylic acid

a) (S) -tert-Butyl 2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate 1,1-dimethoxy-N, N-dimethylmethanamine (12 A mixture of 4 ml, 94 mmol) and (S) -tert-butyl 4-methoxy-3-oxopentanoate (18.9 g, 94 mmol) was stirred at 120 ° C. for 1.5 hours. Then a solution of 5-chloro-1H-pyrazol-3-amine (11.0 g, 94 mmol) in EtOH (100 ml) was added and the resulting mixture was stirred at 85 ° C. for 1 hour. The reaction mixture is concentrated and the residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 100/0 to 70/30) to give (S) -tert-butyl 2-chloro-7- (1 -Methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate was obtained. M / z = 312 to 314 [M + H] +, Rt = 1.31 minutes (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.65 (s, 1 H), 7.03 (s, 1H), 5.26 (q, 1H), 3.22 (s, 3H), 1.62 (d, 3H), 1.55 (s, 9H).

b) (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (S) -tert-butyl 2-chloro-7- (1-methoxyethyl) To a solution of pyrazolo [1,5-a] pyrimidine-6-carboxylate (15.0 g, 48.1 mmol) in DCM (75 ml) was added TFA (74 ml) at room temperature. The reaction mixture was stirred overnight and concentrated. Et ₂ O is added to the residue and the suspension is evaporated to dryness to give (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid I got M / z = 256-258 [M + H] +, Rt = 0.57 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.72 (s, 1 H), 7.03 (s, 1H), 5.40 (q, 1H), 3.20 (s, 3H), 1.64 (d, 3H).
D2: 2-Chloro-7- (2-methoxypropan-2-yl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

tert-butyl 4-methoxy-4-methyl-3-oxopentanoate is used instead of (S) -tert-butyl 4-methoxy-3-oxopentanoate, as described for compound D1, 2 -Chloro-7- (2-methoxypropan-2-yl) pyrazolo [1,5-a] pyrimidin-6-carboxylic acid was prepared analogously. M / z = 270 to 272 [M + H] +, Rt = 0.77 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.55 (s, 1 H), 6.99 (s, 1H), 3.21 (s, 3H), 1.80 (s, 6H).
D3: 2-Chloro-7- (1-methylcyclopropyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

tert-Butyl 3- (1-methylcyclopropyl) -3-oxopropanoate is used instead of (S) -tert-butyl 4-methoxy-3-oxopentanoate, as described for D1, 2-Chloro-7- (1-methylcyclopropyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid was similarly prepared. Step a) was carried out at 80 ° C. for 41 hours. M / z = 252 [M + H] +, Rt = 0.75 minutes (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 13.7 (s, 1 H), 8. 77 (s, 1 H) , 7.00 (s, 1 H), 1.53 (s, 3 H), 1. 10 (t, 2 H), 0.91 (t, 2 H).

  The following compounds were prepared analogously:

D46: (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

a) Ethyl 2- (ethoxymethylene) -4-methyl-3-oxopentanoate ethyl isobutyryl acetate (9.0 g, 56.9 mmol), triethyl orthoformate (18.9 ml, 114 mmol) and Ac ₂ O ( 10.7 ml (114 mmol) were stirred at 135 ° C. overnight. The solution was concentrated (16 mbar / 60 ° C.) to give ethyl 2- (ethoxymethylene) -4-methyl-3-oxopentanoate as a cis / trans mixture. M / z = 215 [M + H] +, Rt = 0.93 and 0.99 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) 7.84 and 7.66 (2 s, 1 H), 4.27-4.06 (m, 4H), 3.12-3.05 (m, 1H), 1.27-1.15 (m, 6H), 1.03-0.98 (m, 6H).

b) (ethyl 2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-carboxylate Ethyl 2- (ethoxymethylene) -4-methyl-3-oxopentanoate in EtOH (130 ml) (11.8 g, 55.1 mmol) and 5-chloro-1H-pyrazol-3-amine (6.15 g, 52.3 mmol) were stirred overnight at 80 ° C. Water is added to the reaction mixture and the aqueous phase is AcOEt. The organic phase is washed with saturated aqueous NaHCO ₃ solution, water and brine, dried over Na ₂ SO ₄ , filtered and concentrated The crude product is flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 9/1) to give ethyl 2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidi -6-carboxylate .M / z = 268~270 [M + H] +, Rt = 1.27 min (UPLC method ^{B2), 1 H NMR (400} MHz, DMSO-d 6) δ 8.80 (s, 1H), 7.00 (s, 1 H), 4. 40-4. 33 (m, 1 H), 4. 37 (q, 2 H), 1.31 (d, 6 H), 1. 36 (t, 3 H).

c) 2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidine-6-carboxylate Ethyl 2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine-6-carboxylate (10. 5 g, 39.3 mmol) was dissolved in EtOH (100 ml) and 2N NaOH (39.3 ml, 79 mmol) was added. The reaction mixture was stirred at 60 ° C. for 3 hours. The EtOH was evaporated, AcOEt was added and the mixture was acidified with 1 M aqueous HCl to give a white suspension. The solid was filtered off, washed with water and dried in vacuo. The resulting residue was treated with AcOEt and extracted with saturated aqueous NaHCO ₃ solution. Separate the aqueous phase, acidify to pH = 2, filter the precipitate and wash with cold AcOEt to give 2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid The M / z = 240 to 242 [M + H] +, Rt = 0.83 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.83 (s, 1 H), 6.98 (s, 1 H), 4.58-4. 47 (m, 1 H), 1.51 (d, 6 H).

  The following compounds were prepared analogously:

D57: 2-chloro-7-((4-methylmorpholin-3-yl) methyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

a) tert-Butyl 3-((6- (tert-butoxycarbonyl) -2-chloropyrazolo [1,5-a] pyrimidin-7-yl) methyl) morpholine-4-carboxylate tert-butyl 3- (4-) (Tert-butoxy) -2,4-dioxobutyl) morpholine-4-carboxylate was used in place of (S) -tert-butyl 4-methoxy-3-oxopentanoate and was described in compound D1 step a) As before, tert-butyl 3-((6- (tert-butoxycarbonyl) -2-chloropyrazolo [1,5-a] pyrimidin-7-yl) methyl) morpholine-4-carboxylate was similarly prepared. M / z = 453-455 [M + H] +, Rt = 1.36 min (UPLC method B2).

b) tert-Butyl 2-chloro-7- (morpholin-3-ylmethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate 4N HCl in 1,4-dioxane (1.0 ml, 4.0 mmol) Of tert-butyl 3-((6- (tert-butoxycarbonyl) -2-chloropyrazolo [1,5-a] pyrimidin-7-yl) methyl) morpholine-4-carboxylate (100 mg, 0.22 mmol) at room temperature The mixture was stirred for 2 hours. The solvent was evaporated to give tert-butyl 2-chloro-7- (morpholin-3-ylmethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate. M / z = 353-355 [M + H] +, Rt = 0.72 min (UPLC method B2).

c) tert-Butyl 2-chloro-7-((4-methylmorpholin-3-yl) methyl) pyrazolo [1,5-a] pyrimidin-6-carboxylate tert-butyl 2 in MeOH (4.5 ml) -Chloro-7- (morpholin-3-ylmethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate (70 mg, 0.18 mmol), 37% aqueous formaldehyde solution (40 μl, 0.54 mmol) and AcOH (15 μl) , 0.27 mmol) was added. After 30 minutes at room temperature, NaBH (OAc) ₃ (57 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. Then 37% aqueous formaldehyde (40 μl, 0.54 mmol) was added and after stirring for 30 minutes NaBH (OAc) ₃ (57 mg, 0.27 mmol) was added. The mixture was stirred for an additional hour. The solvent was removed and the residue was treated with saturated aqueous NaHCO ₃ solution and extracted with AcOEt. The organic phase is dried on an IST cartridge and, after removing the solvent, tert-butyl 2-chloro-7-((4-methylmorpholin-3-yl) methyl) pyrazolo [1,5-a] pyrimidine-6-carboxy I got a rate. M / z = 367 to 369 [M + H] +, Rt = 0.78 min (UPLC method B2).

d) 2-Chloro-7-((4-methylmorpholin-3-yl) methyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid tert-butyl 2-chloro-7-((4-methylmorpholine) (3-yl) methyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate (S) -tert-butyl 2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine 2-chloro-7-((4-methylmorpholin-3-yl) methyl) pyrazolo [1,5-a] pyrimidine, as described for compound D1 step b), in place of -6-carboxylate The -6-carboxylic acid was similarly prepared. M / z = 311-313 [M + H] +, Rt = 0.43 min (UPLC method B2).
D58: (S) -2-chloro-7- (1-methylpiperidin-2-yl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

(S) -tert-Butyl 2- (3- (tert-butoxy) -3-oxopropanoyl) piperidine-1-carboxylate tert-Butyl 3- (4- (tert-butoxy) -2,4-dioxobutyl ) (S) -2-chloro-7- (1-methylpiperidin-2-yl) pyrazolo [1,5-a] pyrimidine as described for compound D57, used in place of morpholine-4-carboxylate The -6-carboxylic acid was similarly prepared. Step a) was performed at 80 ° C. overnight. M / z = 295 to 297 [M + H] +, Rt = 0.57 min (UPLC method B2).
D59: (S) -7- (1-((tert-butoxycarbonyl) (methyl) amino) ethyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylic acid

a) (S) -tert-Butyl 7- (1-((tert-butoxycarbonyl) (methyl) amino) ethyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylate 1,1-dimethoxyamine -N, N-dimethylmethanamine (2.77 ml, 20.8 mmol) and (S) -tert-butyl 4-((tert-butoxycarbonyl) (methyl) amino) -3-oxopentanoate (6.28 g The mixture of 20.8 mmol) was stirred at 120 ° C. for 1 hour. Then a solution of 5-chloro-1H-pyrazole-3-amine (2.45 g, 20.8 mmol) in EtOH (25 ml) was added and the reaction mixture was stirred at 80 ° C. for 2 hours. The mixture is concentrated and the crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 7/3) to give (S) -tert-butyl 7- (1-((tert-butoxycarbonyl) ) (Methyl) amino) ethyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylate was obtained. M / z = 411 to 413 [M + H] +, Rt = 1.53 minutes (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.72 (s, 1 H), 7.03 (s, 1H), 5.77 (m, 1H), 2.94 (s, 3H), 1.67 (d, 3H), 1.55 (s, 9H), 1.40 to 0.83 (m, 9H).

b) (S) -7- (1-((tert-butoxycarbonyl) (methyl) amino) ethyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylic acid (S) -tert-butyl 7 -(1-((tert-Butoxycarbonyl) (methyl) amino) ethyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylate (680 mg, 1.66 mmol) and TFA (2.55 ml, 33 mmol The mixture of) was stirred overnight. The mixture was concentrated, DCM was added and the mixture was concentrated again. The residue is dissolved in THF (10 ml) and 2N aqueous Na ₂ CO ₃ (10 ml) is added followed by di-tert-butyl dicarbonate (0.429 mg, 1.97 mmol) and the reaction mixture is stirred for 48 hours did. The mixture was concentrated, acidified (to pH 4-5) with 1 N aqueous citric acid and extracted with AcOEt. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 0/1) to give (S) -7- (1-((tert-butoxycarbonyl) (methyl) amino) ethyl) 2-Chloropyrazolo [1,5-a] pyrimidine-6-carboxylic acid was obtained. M / z = 355-357 [M + H] +, Rt = 1.00 min (UPLC method B1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.80 (s, 1 H), 7.02 (s, 1 H), 6.05-5.94 (m, 1 H), 2.99 (s, 3 H), 1.67 (d, 3 H) ), 1.26 + 0.88 (2s, 9H)
D60: (R) -2-chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

a) (R) -tert-butyl 2-chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate 1,1-dimethoxy-N, N-dimethyl A mixture of methanamine (1.19 ml, 8.51 mmol) and (R) -tert-butyl 4-methoxy-5-methyl-3-oxohexanoate (1.96 g, 8.51 mmol) at 120 ° C. Stir for hours. The mixture was evaporated to dryness in vacuo. Then, a solution of 5-chloro-1H-pyrazole-3-amine (500 mg, 4.25 mmol) in EtOH (35 ml) was added to the above obtained intermediate, and the reaction mixture was stirred at 80 ° C. for 45 hours. The mixture is concentrated and the residue is dissolved in AcOEt / water. The phases were separated and the organic layer was washed with saturated aqueous NaHCO ₃ solution, water and brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 9/1) to give (R) -tert-butyl 2-chloro-7- (1-methoxy-2-methylpropyl) The pyrazolo [1,5-a] pyrimidine-6-carboxylate was obtained. M / z = 340-342 [M + H] +, Rt = 1.40 min (UPLC method B2).

b) (R) -2-chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (R) -tert-butyl 2-chloro-7- (b) 1-Methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate (1.2 g, 2.97 mmol) in DCM (10 ml) with TFA (9.1 ml, 119 mmol) Added. The reaction mixture was stirred at room temperature for 1 hour. The mixture is evaporated, the residue is dissolved in toluene, evaporated and evaporated to dryness in vacuo to give (R) -2-chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a]. Pyrimidine-6-carboxylic acid was obtained. M / z = 284 to 286 [M + H] +, Rt = 0.81 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 13.81 (s, 1 H), 8.79 (s, 1H), 7.03 (s, 1H), 5.10 (d, 1H), 3.17 (s, 3H), 2.76 (m, 1H), 1.10 (d, 3H), 0.68 (d, 3H).
D61: (S) -7- (1-methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid

a) (S) -tert-Butyl 7- (1-methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxylate 1,1-dimethoxy-N, N-dimethylmethanamine (0. 1). A mixture of 66 ml, 4.94 mmol) and (S) -tert-butyl 4-methoxy-3-oxopentanoate (1.0 g, 4.94 mmol) was stirred at 120 ° C. for 1 hour. Then, a solution of 5-methyl-1H-pyrazol-3-amine (0.48 g, 4.94 mmol) in EtOH (5 ml) was added and the reaction mixture was stirred at 80 ° C. for 1.5 hours. The mixture is concentrated and the crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 8/2) to give (S) -tert-butyl 7- (1-methoxyethyl) -2 Methyl pyrazolo [1,5-a] pyrimidine-6-carboxylate is obtained. M / z = 292 [M + H] +, Rt = 1.19 minutes (UPLC method B1).

b) (S) -7- (1-methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid (S) -tert-butyl 7- (1-methoxyethyl) -2-methylpyrazolo To a solution of [l, 5-a] pyrimidine-6-carboxylate (1.07 g, 3.67 mmol) in DCM (5 ml) was added TFA (5.66 ml, 73.5 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture is evaporated, the residue is dissolved in Et ₂ O, the solid is filtered, washed with Et ₂ O, dried under HV and (S) -7- (1-methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid was obtained. The filtrate was concentrated, basified with saturated aqueous NaHCO ₃ solution and extracted with AcOEt. The organic layer is dried over Na ₂ SO ₄ , filtered and evaporated to a further batch of (S) -7- (1-methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid I got M / z = 236 [M + H] +, Rt = 0.50 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 13.47 (bs, 1H), 8.58 (s, 1H) , 6.65 (s, 1 H), 5. 46 (q, 1 H), 3. 19 (s, 3 H), 2. 47 (s, 3 H), 1. 65 (d, 3 H).
D62: (S) -2-fluoro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

a) (S) -tert-Butyl 2-fluoro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylate 1,1-dimethoxy-N, N-dimethylmethanamine (1 A mixture of .31 ml, 9.89 mmol) and (S) -tert-butyl 4-methoxy-3-oxopentanoate (0.40 g, 1.98 mmol) was stirred at 120 ° C. for 1 hour. Then, a solution of 5-fluoro-1H-pyrazol-3-amine (0.30 mg, 2.97 mmol) in EtOH (6.6 ml) was added and the reaction mixture was stirred at 80 ° C. overnight. The mixture was diluted with water and extracted twice with AcOEt. The organic layer was washed with saturated aqueous NaHCO ₃ solution, water and brine, dried over a phase separation cartridge (IST) and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 9/1) to give (S) -tert-butyl 2-fluoro-7- (1-methoxyethyl) pyrazolo [1,1 5-a] Pyrimidin-6-carboxylate was obtained. M / z = 296 [M + H] +, Rt = 1.21 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.65 (s, 1 H), 6.67 (d, 1 H) , 5.20 (q, 1 H), 3.21 (s, 3 H), 1.61 (d, 3 H), 1.55 (s, 9 H).

b) (S) -2-fluoro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (S) -tert-butyl 2-fluoro-7- (1-methoxyethyl) To a solution of pyrazolo [1,5-a] pyrimidine-6-carboxylate (0.67 g, 2.25 mmol) in DCM (5 ml) was added TFA (3.47 ml, 45.0 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was evaporated, dissolved in toluene and co-evaporated. The residue is dissolved in Et ₂ O, the solid is filtered, washed with Et ₂ O, dried under HV and (S) -2-fluoro-7- (1-methoxyethyl) pyrazolo [1,5 -A] Pyrimidin-6-carboxylic acid was obtained. M / z = 240 [M + H] +, Rt = 0.57 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 13.63 (bs, 1H), 8.73 (s, 1H) , 6.67 (d, 1 H), 5. 37 (q, 1 H), 3. 19 (s, 3 H), 1.63 (d, 3 H).
D63: 2-chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid

a) tert-Butyl 3- (6- (tert-butoxycarbonyl) -2-chloropyrazolo [1,5-a] pyrimidin-7-yl) morpholine-4-carboxylate 1,1-dimethoxy-N, N-dimethyl Methaneamine (1.21 ml, 9.11 mmol) and (S) -tert-butyl 3- (3- (tert-butoxy) -3-oxopropanoyl) morpholine-4-carboxylate (600 mg, 1.822 mmol) The mixture was stirred at 120 ° C. for 1 hour. Then a solution of 5-chloro-1H-pyrazol-3-amine (321 mg, 2.73 mmol) in EtOH (6.1 ml) was added and the reaction mixture was stirred at 80 ° C. overnight and then at 100 ° C. for 5 hours. The mixture was evaporated, the residue redissolved in tBuOH (6.1 ml) and the reaction mixture was stirred at 120 ° C. for 2 days. 5-Chloro-1 H-pyrazole-3-amine (321 mg, 2.73 mmol) was then added to the reaction mixture, which was stirred at 120 ° C. for 2 hours. The mixture was diluted with water and extracted twice with AcOEt. The organic layer was washed with saturated aqueous NaHCO ₃ solution, water and brine, dried over a phase separation cartridge (IST) and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 4/1) to give tert-butyl 3- (6- (tert-butoxycarbonyl) -2-chloropyrazolo [1,5- a] Pyrimidin-7-yl) morpholine-4-carboxylate was obtained. Chiral analysis indicated that the stereocenter was essentially completely racemized, which was thought to have already occurred in the previous step. M / z = 439-441 [M + H] +, Rt = 1.36 minutes (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.75 (s, 1 H), 7.05 (s, 1H), 5.75 (m, 1H), 4.12 (t, 1H), 3.99 (m, 2H), 3.86 (m, 1H), 3.69 (m, 1H), 3.49 (m, 1H), 1.55 (s, 9H) ), 0.88 (bs, 9H).

b) 2-Chloro-7- (morpholin-3-yl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid tert-butyl 3- (6- (tert-butoxycarbonyl) -2-chloropyrazolo [1,1 5-a] Pyrimidin-7-yl) morpholine-4-carboxylate (275 mg, 0.63 mmol) in 1,4-dioxane (3 ml) in 4 M HCl in 1,4-dioxane (1.57 ml, 6 .27 mmol) were added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated and the residue redissolved in DCM (3 ml). TFA (0.96 ml, 12.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was evaporated, dissolved in toluene and co-evaporated. The residue is dissolved in Et ₂ O, the solid is filtered, washed with Et ₂ O, dried over HV and 2-chloro-7- (morpholin-3-yl) pyrazolo [1,5-a] Pyrimidine-6-carboxylic acid was obtained. M / z = 283-285 [M + H] +, Rt = 0.48 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.05 (s, 1 H), 7.11 (s, 1H), 5.74 (m, 1H), 4.14-4.05 (m, 4H), 3.79 (m, 2H).

c) 7- (4- (tert-Butoxycarbonyl) morpholin-3-yl) -2-chloropyrazolo [1,5-a] pyrimidin-6-carboxylic acid 2-chloro-7- (morpholin-3-yl) pyrazolo A solution of [1,5-a] pyrimidine-6-carboxylic acid (200 mg, 0.71 mmol) in THF (2 ml) / 2N aqueous Na ₂ CO ₃ solution (2 ml) at room temperature Boc ₂ O (0.2 ml, 0 .85 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. The mixture is filtered, the filtrate is concentrated, the residue is frozen and lyophilized to give 7- (4- (tert-butoxycarbonyl) morpholin-3-yl) -2-chloropyrazolo [1,5-a] pyrimidine. The -6-carboxylic acid was obtained. M / z = 383-385 [M + H] +, Rt = 0.88 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.82 (s, 1 H), 6.75 (s, 1H), 6.50 (m, 1H), 4.10-3.97 (m, 2H), 3.91-3.85 (m, 3H), 3.50-3.44 (m, 1H), 0.83 (bs, 9H).
D64: (S) -7- (1-((tert-butoxycarbonyl) (methyl) amino) -2-methylpropyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylic acid

In step a), (S) -tert-butyl 4-((tert-butoxycarbonyl) (methyl) amino) -5-methyl-3-oxohexanoate is reacted with (S) -tert-butyl 3- (3- (3- (3- (3- (3- (S) -7- (1-((tert-butoxycarbonyl) (methyl) amino) -2 used in place of tert-butoxy) -3-oxopropanoyl) morpholine-4-carboxylate and similar to D63 -Methylpropyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylic acid was prepared. M / z = 383-385 [M + H] +, Rt = 1.20 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.57 (s, 1 H), 6.74 (s, 1H), 6.12 (m, 1H), 3.08 (m, 1H), 2.90 (s, 3H), 1.32 (s, 9H), 0.98 (d, 3H), 0.77 (d, 3H).
Part E: Synthesis of anilines, amino-pyridines and pyrrolidones E1: 6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-amine

a) 5-Nitro-2- (2H-1,2,3-triazol-2-yl) -3- (trifluoromethyl) pyridine 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (1 .0g, 4.41mmol) and _K 2 _CO 3 (1.22g, to a solution medium THF (5 ml) in 8.83mmol), 2H-1,2,3- triazole (0.31 ml, 5.30 mmol) added did. The reaction mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 100/0 to 50/50) to give 5-nitro-2- (2H-1,2,3-triazol-2-yl) -3- (trifluoromethyl) pyridine was obtained. M / z = 260 [M + H] +, Rt = 0.88 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.69 (d, 1 H), 9. 17 (d, 1 H) , 8.37 (s, 2H).

b) 6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-amine 5-nitro-2- (2H-1,2,3-triazole-2) -Yl) -3- (trifluoromethyl) pyridine (770 mg, 2.97 mmol) in 1.25 M HCl (48 ml, 59 mmol) in MeOH at room temperature with tin (II) chloride (2.82 g, 14.9 mmol) ) Was added little by little. The reaction was stirred at room temperature for 2 hours. 4N aqueous NaOH solution was added and the solution was extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 100/0 to 0/100) to give 6- (2H-1,2,3-triazol-2-yl) -5- (Trifluoromethyl) pyridin-3-amine was obtained. M / z = 230 [M + H] +, Rt = 0.64 minutes (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.08 (d, 1 H), 8.05 (s, 2 H) , 7.43 (d, 1 H), 6. 39 (s, 2 H).
E2: 5-methoxy-6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine

2-chloro-3-methoxy-5-nitropyridine is used in place of 2-chloro-5-nitro-3- (trifluoromethyl) pyridine, as described for E1, 5-methoxy-6- (2H -1,2,3-Triazol-2-yl) pyridin-3-amine was prepared analogously. Perform step a) overnight. M / z = 192 [M + H] +, Rt = 0.35 min (UPLC method B1).
E3: 5-chloro-6- (4-methyl-2H-1,2,3-triazol-2-yl) pyridin-3-amine

Use 4-methyl-2H-1,2,3-triazole instead of 2H-1,2,3-triazole, as described for E1, 5-chloro-6- (4-methyl-2H-1 2,3-Triazol-2-yl) pyridin-3-amine was similarly prepared. Step a) was performed overnight and step b) was performed overnight with 1.25 N HCl in EtOH. M / z = 210 [M + H] +, Rt = 0.65 min (UPLC method B2).
E4: 5- (Difluoromethyl) -6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine

a) (5-Bromo-2-chloropyridin-3-yl) methanol Methyl 5-bromo-2-chloronicotinate (5.92 g, 23.6 mmol) in DCM (70 ml) at room temperature under N ₂ atmosphere Anhydrous CaCl ₂ (10.5 g, 94 mmol) was added followed by portionwise addition of NaBH ₄ (3.57 g, 94 mmol) at 0 ° C. The reaction mixture was stirred at room temperature overnight. THF (70.0 ml) was added and the mixture was stirred at 60 ° C. for 24 hours. 1,4-dioxane (70 ml) was added and the mixture was stirred at 90 ° C. for 28 hours. After cooling to 0 ° C., the reaction mixture was quenched carefully with water and stirred at room temperature overnight. The lithium salt was filtered off through a pad of celite and washed with THF. The filtrate was diluted with water and AcOEt, the organic phase separated and the aqueous phase extracted with AcOEt. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give (5-bromo-2-chloropyridin-3-yl) methanol. M / z = 222/224/226 [M + H] +, Rt = 0.70 min (UPLC method B2). ¹ H NMR (400 MHz, DMSO d ₆ ) δ ppm: 8.47 (m, 1 H), 8.08-8.07 (m, 1 H), 5.69 (t, 1 H), 4.53 (d, 2 H)

b) 5-Bromo-2-chloronicotinaldehyde DCM (250 ml) solution of (5-bromo-2-chloro-3-yl) methanol (5.24 g, in 22.1 mmol), _{N 2} atmosphere _MnO 2 ( 19.2 g, 22.1 mmol) were added. After stirring for 2 hours at room temperature, MnO ₂ (3.85 g, 44.2 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. Then MnO ₂ (1.92 g, 22.1 mmol) was added and the mixture was stirred at room temperature for 4 hours. The MnO ₂ was filtered off through a pad of celite, washed with DCM and the filtrate was evaporated. The residue was purified by flash column chromatography on silica gel (hexane / TBME 1/0 to 3/7) to give 5-bromo-2-chloronicotinaldehyde. Rt = 1.02 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.19 (s, 1 H), 8. 85 (d, 1 H), 8. 39 (d, 1 H).

c) 5-Bromo-2-chloro-3- (difluoromethyl) pyridine 5-bromo-2-chloronicotinaldehyde (2.96 g, 12.8 mmol) in DCM (75 ml), under an atmosphere of N _{2 with} EtOH (0 .075 ml, 1.27 mmol) were added and DAST (3.74 ml, 25.5 mmol) was added dropwise over 5 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0 ° C., the reaction mixture is quenched with saturated aqueous NaHCO ₃ solution, the organic phase is separated and the aqueous phase is extracted with DCM. The combined organic phases were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give 5-bromo-2-chloro-3- (difluoromethyl) pyridine. Rt = 1.02 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.78 (d, 1 H), 8. 40 (d, 1 H), 7. 13 (t, 1 H), ¹⁹ F NMR (400 MHz, DMSO d6): δ ppm: -117.02 / -116.88 (d, 2F).

d) 5-Bromo-3- (difluoromethyl) -2- (2H-1,2,3-triazol-2-yl) pyridine 5-bromo-2-chloro-3- (difluoromethyl) in DMF (5 ml) ) pyridine (1.30 g, 5.0 mmol) and _K 2 _CO 3 (1.38g, to 10.0 mmol), was added under argon IH-1,2,3-triazole (0.38 ml, 6.48 mmol) . The reaction mixture was stirred at 90 ° C. overnight. The suspension was filtered and the filtrate was concentrated. The residue was diluted with ice cold water, extracted with AcOEt, the organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue is purified by flash column chromatography on silica gel (hexane / TBME 1/0 to 1/1) to give 5-bromo-3- (difluoromethyl) -2- (2H-1,2,3-triazole A mixture of -2-yl) pyridine and 5-bromo-3- (difluoromethyl) -2- (1H-1,2,3-triazol-1-yl) pyridine was obtained. M / z = 275/277 [M + H] +, Rt = 0.92 to 0.93 min (UPLC method B2).

e) tert-Butyl (5- (difluoromethyl) -6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) carbamate 5-bromo-3- (difluoromethyl) -2- A mixture of (2H-1,2,3-triazol-2-yl) pyridine and 5-bromo-3- (difluoromethyl) -2- (1H-1,2,3-triazol-1-yl) pyridine (1 .09G, to 3.96 mmol), tert-butyl carbamate _{(0.93mg, 7.93mmol), Xantphos (} 206mg, 0.36mmol), Cs 2 CO 3 (2.58g, 7.93mmol) and _Pd 2 dba ₃ (109 mg, 0.12 mmol) was added. The mixture was purged with argon and 1,4-dioxane (50 ml) was added. The reaction mixture was stirred at 90 ° C. overnight. The suspension was filtered, the filtrate was diluted with DCM and water, the organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (hexane / TBME 1/0 to 1/1) to give tert-butyl (5- (difluoromethyl) -6- (2H-1,2,3-) Triazol-2-yl) pyridin-3-yl) carbamate was obtained. M / z = 312/313 [M + H] +, Rt = 1.02 min (UPLC method B2). ¹ H NMR (400 MHz, DMSO d ₆ ) δ ppm: 10.16 (s, 1 H), 8. 73 (d, 1 H), 8. 47 (d, 1 H), 8. 19 (s, 2 H), 7. 26 (t, 1 H), 1.52 ( s, 9H).

f) 5- (Difluoromethyl) -6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine tert-butyl (5- (difluoromethyl) -6- (2H-1,2) 4, 3-Triazol-2-yl) pyridin-3-yl) carbamate (0.68 g, 2.13 mmol), 4N HCl in 1,4-dioxane (5.3 ml, 21.3 mmol) is added and the reaction mixture The mixture was stirred at room temperature for 1.5 days. The solvent is evaporated, the residue is dissolved in DCM, washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness, 5- (difluoromethyl) -6- ( 2H-1,2,3-Triazol-2-yl) pyridin-3-amine was obtained. M / z = 212/213 [M + H] +, Rt = 0.55 min (UPLC method B2). ¹ H NMR (400 MHz, DMSO d ₆ ) δ ppm: 8.08 (d, 2 H), 7.99 (s, 1 H), 7.34 (d, 1 H), 6. 97 (t, 1 H), 6.14 (bs, 2 H), ¹⁹ F NMR (400 MHz, DMSO d6): δ ppm: -113.89 / -114.03 (d, 2F).
E5: 5-chloro-6-ethoxypyridin-3-amine

a) tert-Butyl (5-chloro-6-ethoxypyridin-3-yl) carbamate To 5-chloro-6-ethoxynicotinic acid (0.40 mg, 1.98 mmol) in tBuOH (10 ml), DPPA (0. 1). 51 ml, 2.38 mmol) and _Et 3 N (0.55ml, _3.97mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then at 100 ° C. for 4 hours. After cooling to room temperature, AcOEt was added and the organic phase was washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column (cyclohexane / AcOEt 100/0 to 80/20) to give tert-butyl (5-chloro-6-ethoxypyridin-3-yl) carbamate. M / z = 273-275 [M + H] +, Rt = 1.27 min (UPLC method B1).

b) 5-Chloro-6-ethoxypyridin-3-amine tert-butyl (5-chloro-6-ethoxypyridin-3-yl) carbamate (0.42 g, 1.0 mmol) in MeOH (5 ml), 1 4 N HCl in 1, 4-dioxane (1.27 ml, 5.1 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated. Et ₂ O was added to the residue and the solid was filtered and rinsed with Et ₂ O to give 5-chloro-6-ethoxypyridin-3-amine. M / z = 173 to 175 [M + H] +, Rt = 0.75 minutes (UPLC method B1).
E6: 6-methoxy-5- (trifluoromethyl) pyridin-3-amine

a) 2-methoxy-5-nitro-3- (trifluoromethyl) pyridine 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (2.0 g, 8.83 mmol) in THF (5 ml) At 0 ° C., sodium methoxide (1.80 ml, 9.71 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was evaporated, dissolved in water and cooled at 0 ° C. The precipitate was filtered, washed with cold water and dried under HV to give 2-methoxy-5-nitro-3- (trifluoromethyl) pyridine. M / z = 223 [M + H] +, Rt = 1.11 minutes (UPLC method B3).

b) 6-Methoxy-5- (trifluoromethyl) pyridin-3-amine 2-methoxy-5-nitro-3- (trifluoromethyl) pyridine (1.84 g, 8.28 mmol) in AcOH (30 ml) Iron powder (4.63 g, 83 mmol) was added at room temperature and the reaction mixture was stirred at room temperature overnight. Celite was added and the solvent was evaporated to dryness. The residue was dissolved in DCM and saturated aqueous NaHCO ₃ , sonicated and filtered through a pad of celite. The cake was washed with DCM and the binary system was separated. The aqueous phase is extracted with DCM, the combined organic phases are washed with water, dried over Na ₂ SO ₄ , filtered and concentrated to dryness under vacuum, 6-methoxy-5- (trifluoromethyl) pyridine -3- amine was obtained. M / z = 193 [M + H] +, Rt = 0.76 minutes (UPLC method B3), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.75 (m, 1 H), 7.33 (d, 1 H) , 5.17 (s, 2H), 3.82 (s, 3H).
E7: 2- (5-amino-3- (trifluoromethyl) pyridin-2-yl) isothiazolidine 1,1-dioxide

a) 2- (5-Nitro-3- (trifluoromethyl) pyridin-2-yl) isothiazolidine 1,1-dioxide 2-chloro-5-nitro-3-trile in 1,4-dioxane (12 ml) fluoromethyl pyridine (0.56 g, 2.48 mmol) and isothiazolidine 1,1-dioxide (0.60 g, 4.96 mmol) _{in, Cs 2 CO 3 (0.81g,} 2.48mmol) was added and the argon The mixture was blown into for 10 minutes. Then Xantphos (287mg, 0.50mmol) and _{Pd 2 (dba) 3 (114mg} , 0.124mmol) was added. The reaction mixture was stirred at 140 ° C. for 40 minutes in a microwave oven. The mixture was filtered through a pad of celite and the solvent was evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 100/0 to 50/50) to give 2- (5-nitro-3- (trifluoromethyl) pyridin-2-yl) isothiazolidine 1,1-dioxide was obtained. M / z = 312 [M + H] +, Rt = 0.87 min (UPLC method B2).

b) 2- (5-Amino-3- (trifluoromethyl) pyridin-2-yl) isothiazolidine 1,1-dioxide 2- (5 in 1.25 N HCl (11.9 ml, 21.9 mmol) in EtOH -Nitro-3- (trifluoromethyl) pyridin-2-yl) isothiazolidine 1,1-dioxide (0.34 g, 1.09 mmol) at room temperature with tin (II) chloride (1.04 g, 5.46 mmol) Was added little by little. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated, diluted with DCM, treated with 1 N NaOH, extracted with DCM, dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH 1/0 to 9/1) to give 2- (5-amino-3- (trifluoromethyl) pyridin-2-yl) isothiazolidine 1 , 1-dioxide was obtained. M / z = 282 [M + H] +, Rt = 0.65 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.03 (d, 1 H), 7.26 (d, 1 H) , 6.02 (bs, 2H), 3.68 (t, 2H), 3.20 (t, 2H), 2.44 (m, 2H).
E8: 3-Amino-1-methyl-5- (trifluoromethyl) pyridin-2 (1H) -one

a) 1-methyl-3-nitro-5- (trifluoromethyl) pyridin-2 (1H) -one 3-nitro-5- (trifluoromethyl) -pyridin-2-ol (30 ml) in dry DMF To 1.97 g, 9.46 mmol) and K ₂ CO ₃ (2.62 g, 18.9 mmol) at 0 ° C. is added dropwise iodomethane (0.89 ml, 14.2 mmol) and the reaction mixture is brought to 1.5 at room temperature. Stir for hours. The mixture was poured onto ice / water and extracted with AcOEt. The combined organic phases are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 1-methyl-3-nitro-5- (trifluoromethyl) pyridine-2 (1H)-. Got on. M / z = 223 [M + H] +, Rt = 0.68 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.89 (m, 1H), 8.68 (m, 1H) , 3.61 (s, 3H).

b) 3-Amino-1-methyl-5- (trifluoromethyl) pyridin-2 (1H) -one 1-methyl-3-nitro-5- (trifluoromethyl) pyridine-2 (30 ml) in EtOH (30 ml) IH) - on (1.41 g, the 6.33mmol), 7M _NH 4 Cl solution (9.0 ml, 63 mmol) and iron powder (1.06 g, 19.0 mmol) was added. The reaction mixture was heated to reflux for 1 h with vigorous stirring. After cooling to room temperature, the mixture was filtered through a pad of celite, rinsed with hot EtOH, and the filtrate was evaporated to dryness. Et ₂ O was added to the residue and the mixture sonicated and filtered. The filtrate was evaporated to dryness to give 3-amino-1-methyl-5- (trifluoromethyl) pyridin-2 (1H) -one. M / z = 193 [M + H] +, Rt = 0.64 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.54 (m, 1H), 6.50 (m, 1H) , 5.55 (bs, 2H), 3.49 (s, 3H).
E9: 3-amino-5-chloro-1-methylpyridin-2 (1H) -one

a) 5-Chloro-1-methyl-3-nitropyridin-2 (1H) -one 5-chloro-2-hydroxy-3-nitropyridine (15.0 g, 86 mmol) in DMF (200 ml) at 0 ° C. Then NaH (4.13 g, 103 mmol) was added portionwise and the reaction mixture was stirred at 0 ° C. for 1 h. Iodomethane (8.06 ml, 129 mmol) was added and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated, water was added and the mixture was extracted with AcOEt. The organic phase was washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness to give 5-chloro-1-methyl-3-nitropyridin-2 (1H) -one. M / z = 189 to 191 [M + H] +, Rt = 0.55 min (UPLC method B4).

b) 3-Amino-5-chloro-1-methylpyridin-2 (1H) -one 5-chloro-1-methyl-3-nitropyridin-2 (1H) -one (14.6 g) in MeOH (300 ml) To 78 mmol) was added Raney Nickel (4 g) in EtOH. The reaction mixture was stirred at room temperature under H ₂ atmosphere for 8 hours. The mixture was filtered through celite and evaporated to dryness to give 3-amino-5-chloro-1-methylpyridin-2 (1H) -one. M / z = 159-161 [M + H] +, Rt = 0.51 minutes (UPLC method B4).
E10: 5-amino-3-chloro-1-methyl-6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one

a) 2,3,6-Trichloro-5-nitropyridine To fuming HNO ₃ (136 ml) at 0 ° C. add H ₂ SO ₄ (111 ml) and 2,3,6-trichloropyridine (24.2 g, 133 mmol) did. The reaction mixture was allowed to warm to room temperature and then stirred at 100 ° C. overnight. After cooling to 0 ° C., the mixture is poured onto ice water. The insoluble material was collected by filtration to give 2,3,6-trichloro-5-nitropyridine. Rt = 1.07 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.06 (s, 1 H).

b) 3,6-Dichloro-5-nitropyridin-2 (1H) -one KOH in 2,3,6-trichloro-5-nitropyridine (7.00 g, 30.8 mmol) in dry tBuOH (80 ml) (5.18 g, 92 mmol) was added and the reaction mixture was stirred at room temperature over the weekend. The solvent was evaporated and the remaining solid was partitioned between AcOEt and 2N aqueous HCl. The resulting suspension was sonicated and filtered. The organic phase was separated, the aqueous phase was extracted with AcOEt, and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. To the residue is added AcOEt, the suspension is filtered and the filtrate is evaporated under HV to give 3,6-dichloro-5-nitropyridin-2 (1H) -one and 5,6-dichloro-3- A mixture of nitropyridin-2 (1H) -one was obtained. M / z = 207/209/211 [M-H]-, Rt = 0.57 to 0.65 min (UPLC method B2).

c) 3-Chloro-5-nitro-6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one To 1H-pyrazole (2.68 g, 39.4 mmol) in dry THF (120 ml), NaH (1.62 g, 40.4 mmol, 60% in mineral oil) was added portionwise at -10 <0> C and the reaction mixture was stirred at room temperature overnight. A mixture of 3,6-dichloro-5-nitropyridin-2 (1H) -one and 5,6-dichloro-3-nitropyridin-2 (1H) -one (2.51 g, 9.85 mmol) is added in small portions Then THF (60 ml) was added. The reaction mixture was stirred at room temperature for 4 hours, quenched carefully with water and the mixture was evaporated to dryness. The remaining solid was partitioned between AcOEt and 2N aqueous HCl. The resulting suspension was sonicated and filtered. The organic phase was separated, the aqueous phase was extracted with AcOEt, and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. To the residue is added DCM, the suspension is filtered and the filtrate is evaporated under HV to give 3-chloro-5-nitro-6- (1H-pyrazol-1-yl) pyridine-2 (1H)-. A mixture of on and 5-chloro-3-nitro-6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one was obtained. M / z = 241/243 [M + H] +, Rt = 0.61 to 0.66 min (UPLC method B2).

d) 3-Chloro-1-methyl-5-nitro-6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one 3-chloro-5-nitro-6- (1H-pyrazole-1) (I)) Pyridine-2 (1H) -one and 5-chloro-3-nitro-6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one (3.12 g, 7.0 mmol) in dry DMF To a mixture in (50 ml) was added K ₂ CO ₃ (3.01 g, 21.78 mmol) at room temperature and iodomethane (1.02 ml, 16.33 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight. The mixture is poured onto ice-cold water, the suspension is filtered and the solid obtained is dried at 50 ° C. under HV. The solid was suspended in DCM, triturated, sonicated, the suspension filtered and the filtrate concentrated. The residue is purified by two subsequent flash column chromatography on silica gel (1st: hexane / TBME1 / 0 to 0/1, 2nd time: DCM / TBME1 / 0 to 0/1), 3-chloro-1 -Methyl-5-nitro-6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one was obtained. M / z = 255/257 [M + H] +, Rt = 0.96 min (UPLC method B2). ¹ H NMR (400 MHz, DMSO d ₆ ) δ ppm: 8.83 (s, 1 H) 8. 59 (m, 1 H) 7. 95 (m, 1 H), 6. 67 (m, 1 H) 4. 10 (s, 3 H)

e) 5-Amino-3-chloro-1-methyl-6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one 3-chloro-1-methyl-5-nitro in EtOH (18 ml) -6- (1H-pyrazol-1-yl) pyridin-2 (1H) -one (682 mg, 2.68 mmol), 7 M aqueous NH ₄ Cl (3.83 ml, 26.8 mmol) followed by iron powder (2) 450 mg, 8.04 mmol) were added. The reaction mixture was stirred at reflux for 3.5 hours. After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate was concentrated. The resulting solid is treated with Et ₂ O, triturated, sonicated, the suspension is filtered and the filtrate is evaporated to give 5-amino-3-chloro-1-methyl-6- (1H -Pyrazol-1-yl) pyridin-2 (1H) -one is obtained. M / z = 225/227 [M + H] +, Rt = 0.78 min (UPLC method B2). ¹ H NMR (600 MHz, DMSO d ₆ ) δ ppm: 7.99 (d, 1 H), 7.65 (d, 1 H), 7.04 (s, 1 H), 6.43 (t, 1 H), 5.60 (bs, 2 H), 3.86 (3 s, 3H).
E11: 5-chloro-2-((1-methylpyrrolidin-3-yl) oxy) -6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine

a) 3-Chloro-6-((1-methylpyrrolidin-3-yl) oxy) -5-nitro-2- (2H-1,2,3-triazol-2-yl) pyridine in DMF (10 ml) To NaH (97 mg, 2.42 mmol; 60% in mineral oil) at 0 <0> C was added l-methylpyrrolidin-3-ol (229 mg, 2.20 mmol). After stirring for 30 minutes at room temperature, 2,3,6-trichloro-5-nitropyridine (500 mg, 2.20 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature. To NaH (97 mg, 2.42 mmol; 60% in mineral oil) in DMF (5 ml) was added 2H-1,2,3-triazole (157 mg, 2.20 mmol) at 0 ° C. and stirred at room temperature for 10 minutes After that, activated 2H-1,2,3-triazole was added to the reaction mixture at 0 ° C. The resulting reaction mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with AcOEt. The organic phase was washed with brine, dried over Na ₂ SO ₄ and evaporated. The residue is purified by preparative HPLC (method A4) to give 3-chloro-6-((1-methylpyrrolidin-3-yl) oxy) -5-nitro-2- (2H-1,2,3-) Triazol-2-yl) pyridine was obtained. M / z = 325-327 [M + H] +, Rt = 0.56 min (UPLC method B2).

b) 5-chloro-2-((1-methylpyrrolidin-3-yl) oxy) -6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine 3-chloro-6-amine ((1-methylpyrrolidin-3-yl) oxy) -5-nitro-2- (2H-1,2,3-triazol-2-yl) pyridine to 3-chloro-1-methyl-5-nitro-6 5-chloro-2-((1-methylpyrrolidin-3-yl) oxy) as in place of E10 step e), used instead of-(1H-pyrazol-1-yl) pyridin-2 (1H) -one -6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine was prepared. M / z = 295-297 [M + H] +, Rt = 0.49 min (UPLC method B2).
E12: 5-amino-2- (3-methyl-1H-1,2,4-triazol-1-yl) benzonitrile

a) 2- (3-Methyl-1H-1,2,4-triazol-1-yl) -5-nitrobenzonitrile 2-fluoro-5-nitrobenzonitrile (2.37 g, 14 in DMF (20 ml) .3mmol), 3- methyl-1H-1,2,4-triazole (1.18 g, 14.3 mmol) and _{K 2 CO 3 (3.94g, 28.5mmol} ) was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and extracted with AcOEt. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by preparative HPLC (method A4) to give 2- (3-methyl-1H-1,2,4-triazol-1-yl) -5-nitrobenzonitrile. M / z = 230 [M + H] +, Rt = 0.69 min (UPLC method B5).

b) 5-Amino-2- (3-methyl-1H-1,2,4-triazol-1-yl) benzonitrile 2- (3-methyl-1H-1,2,4- in EtOH (75 ml) Triazol-1-yl) -5-nitrobenzonitrile (741 mg, 3.23 mmol) was hydrogenated through H-Cube® (Pd / C cartridge, 30 ° C., 40 bar, 1 ml / min). The resulting solution was evaporated to dryness to give 5-amino-2- (3-methyl-1H-1,2,4-triazol-1-yl) benzonitrile. M / z = 200 [M + H] +, Rt = 0.48 min (UPLC method B6).
E13: 3-chloro-4- (2H-1,2,3-triazol-2-yl) aniline

a) 2- (2-Chloro-4-nitrophenyl) -2H-1,2,3-triazole 2H-1,2,3-triazole (2.0 g, 29 mmol) in DMF (145 mL) at room temperature NaH (1.16 g, 29 mmol, 60% in mineral oil) was added and the mixture was stirred for 1 hour. After cooling to 0 ° C., 2-chloro-1-fluoro-4-nitrobenzene (4.6 g, 26.1 mmol) is added and the reaction mixture is stirred at 0 ° C. for 1.5 hours and then at room temperature for 1.5 hours did. The mixture was quenched with water and extracted with AcOEt. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column (heptane / AcOEt: 90/10 to 50/50) to give 2- (2-chloro-4-nitrophenyl) -2H-1,2,3-triazole. M / z = 225 to 227 [M + H] +, Rt = 0.95 min (UPLC method B3).

b) 3-Chloro-4- (2H-1,2,3-triazol-2-yl) aniline 2- (2-chloro-4-nitrophenyl) -2H-1,2,3 in EtOH (130 mL) -To triazole (2.24 g, 9.97 mmol) at room temperature was added 2 N aqueous HCl (67 mL) and tin (II) chloride (9.5 g, 50 mmol). The white suspension was stirred at 85 ° C. for 45 minutes. After cooling to room temperature, the reaction mixture was added to concentrated aqueous NaOH solution at 0 ° C. and extracted with TBME / EtOH (9/1). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (heptane / AcOEt: 90/10 to 25/75) to give 3-chloro-4- (2H-1,2,3-triazol-2-yl) aniline . M / z = 195-197 [M + H] +, Rt = 0.88 min (UPLC method B3).
E14: 3,5-dichloro-4- (2H-1,2,3-triazol-2-yl) aniline

In analogy to procedure E13 steps a) and b), 3,5-dichloro-4- (3-dichloro-4-fluoro-5-nitrobenzene is used instead of 3-chloro-4-fluoronitro-benzene 2H-1,2,3-Triazol-2-yl) aniline was prepared. Perform step a) overnight. M / z = 229 to 231 [M + H] +, Rt = 0.93 min (UPLC method B3).
E15: 4- (4-amino-2-chlorophenyl) pyrimidin-2-amine

3-Chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (320 mg, 1.26 mmol) in propanol (8 ml), 2-amino-4- Chloropyrimidine (164 mg, 1.26 mmol) and 1 M aqueous Na ₂ CO ₃ solution (3.8 ml, 3.8 mmol) were added. After stirring for 10 minutes, PdCl ₂ (PPh ₃ ) ₂ (44 mg, 0.063 mmol) was added and the reaction mixture was stirred at 80 ° C. overnight. The mixture was quenched with H ₂ O and extracted with AcOEt. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (heptane / AcOEt) to give 4- (4-amino-2-chlorophenyl) pyrimidin-2-amine. M / z = 221 [M + H] +, Rt = 0.54 min (UPLC method B2).
E16: (1- (4-Amino-2-chlorophenyl) -5-methyl-1H-pyrazol-3-yl) methanol

a) Ethyl 1- (2-chloro-4-nitrophenyl) -5-methyl-1H-pyrazole-3-carboxylate 2-chloro-1-fluoro-4-nitrobenzene (1 g, 5.) in DMF (15 ml). 70 mmol), ethyl 3-methylpyrazole-3-carboxylate (0.88 g, 5.70 mmol) and _{K 2 CO 3 (0.95g, 6.84mmol} ) was stirred at room temperature overnight. Water is added, the precipitate is filtered, rinsed with water and dried under HV to give ethyl 1- (2-chloro-4-nitrophenyl) -5-methyl-1H-pyrazole-3-carboxylate The M / z = 310 to 312 [M + H] +, Rt = 1.05 min (UPLC method B2).

b) Ethyl 1- (4-amino-2-chlorophenyl) -5-methyl-1H-pyrazole-3-carboxylate Ethyl 1- (2-chloro-4-nitrophenyl) -5-methyl in AcOH (50 ml) Iron powder (1.80 g, 32 mmol) was added to 1H-pyrazole-3-carboxylate (1.0 g, 3.23 mmol) and the reaction mixture was stirred at room temperature for 2.5 hours. The mixture was evaporated and the residue was treated with DCM and filtered. The organic phase is washed with saturated aqueous NaHCO ₃ solution, water and brine, dried over Na ₂ SO ₄ , filtered and evaporated to give ethyl 1- (4-amino-2-chlorophenyl) -5-methyl-1H-pyrazole. The -3-carboxylate was obtained. M / z = 280-282 [M + H] +, Rt = 0.90 min (UPLC method B2).

c) (1- (4-Amino-2-chlorophenyl) -5-methyl-1H-pyrazol-3-yl) methanol ethyl 1- (4-amino-2-chlorophenyl) -5-methyl in THF (15 ml) to -1H- pyrazole-3-carboxylate (0.81 g, 2.90 mmol), THF in 2M LiAlH ₄ (2.17ml, 4.35mmol) was added dropwise and the reaction mixture was stirred for 1.5 hours at room temperature . The reaction mixture was quenched carefully with water and extracted with AcOEt. The organic phase is washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated (1- (4-amino-2-chlorophenyl) -5-methyl-1H-pyrazol-3-yl) Methanol was obtained. M / z = 238-240 [M + H] +, Rt = 0.61 min (UPLC method B2).
E17: tert-butyl ((1- (4-amino-2-chlorophenyl) -1H-pyrazol-4-yl) methyl) carbamate

tert-Butyl ((1H-pyrazol-4-yl) methyl) carbamate is used in place of ethyl 3-methylpyrazole-3-carboxylate, analogous to E16 steps a) and b) (4-Amino-2-chlorophenyl) -1 H-pyrazol-4-yl) methyl) carbamate was prepared. Step b) was performed overnight at room temperature. M / z = 323-325 [M + H] +, Rt = 0.90 minutes (UPLC method B2).
E18: tert-butyl ((1- (5-amino-3-chloropyridin-2-yl) -1H-pyrazol-4-yl) methyl) carbamate

2,3-Dichloro-5-nitropyridine is used in place of 2-chloro-1-fluoro-4-nitrobenzene, tert-butyl ((1H-pyrazol-4-yl) methyl) carbamate is ethyl 3-methylpyrazole- Tert-Butyl ((1- (5-amino-3-chloropyridin-2-yl) -1H-pyrazole-4), used instead of 3-carboxylate, as described in E16 steps a) and b) -Yl) methyl) carbamate was similarly prepared. Step b) was performed overnight at room temperature. M / z = 324 to 326 [M + H] +, Rt = 0.81 min (UPLC method B2).
E19: (1- (4-Amino-2-chlorophenyl) -5-methyl-1H-pyrazol-3-yl) methanol

a) 5-chloro-7-nitro indoline-2-one H ₂ SO ₄ (20ml) of 5-chloro-oxindole (1.0 g, to _{5.97mmol), H 2 SO 4 (} 20ml) in at 0 ℃ Of KNO ₃ (0.72 g, 7.16 mmol) were added dropwise. After stirring for 15 minutes at 0 ° C., the reaction mixture was stirred for 45 minutes at 90 ° C. The mixture was cooled to room temperature and poured onto ice. The suspension was filtered, rinsed with water and dried under HV to give 5-chloro-7-nitroindolin-2-one. M / z = 211 [M-H]-, Rt = 0.76 min (UPLC method B2).

b) 7-amino-5-chloroindoline-2-one 5-chloro-7-nitroindoline-2-one (1.2 g, 5.64 mmol) in AcOH (80 ml), iron powder (3.15 g, 56.4 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the residue was treated with DCM and filtered. The organic phase was washed with saturated aqueous NaHCO ₃ solution, water and brine, dried over Na ₂ SO ₄ , filtered and evaporated to give ethyl 7-amino-5-chloroindoline-2-one. M / z = 183-185 [M + H] +, Rt = 0.62 min (UPLC method B2).
E20: (1- (4-Amino-2-chlorophenyl) -5-methyl-1H-pyrazol-3-yl) methanol

a) 3-Chloro-2- (1-methyl-1H-pyrazol-5-yl) -5-nitropyridine 2,3-dichloro-5-nitropyridine (0% in 1,4-dioxane (10.5 ml) .30G, to 1.56 mmol), 1-methyl--1H- pyrazole-5-boronic acid pinacol ester (0.32g, 1.56mmol), water (2.4 ml) and _K 2 _CO 3 (1.29g, 9 .3 mmol) was added. Under argon, Pd (PPh ₃ ) ₄ (90 mg, 0.078 mmol) was added and the reaction mixture was stirred in the microwave at 140 ° C. for 20 minutes. Water and AcOEt were added and the organic phase was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash chromatography on silica gel (heptane / AcOEt 85/15 to 15/85) to give 3-chloro-2- (1-methyl-1H-pyrazol-5-yl) -5-nitro Pyridine was obtained. M / z = 239 to 241 [M + H] +, Rt = 0.85 min (UPLC method B2).

b) 5-chloro-6- (1-methyl-1H-pyrazol-5-yl) pyridin-3-amine G32 as described for step b) 5-chloro-6- (1-methyl-1H- Pyrazol-5-yl) pyridin-3-amine was prepared analogously. M / z = 209-211 [M + H] +, Rt = 0.60 minutes (UPLC method B2).
E21: 5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine

a) 3-Chloro-5-nitro-2- (2H-1,2,3-triazol-2-yl) pyridine 2,3-dichloro-5-nitropyridine (1.0 g, 5.18 mmol) and K ₂ CO ₃ (1.43g, 10.4mmol) was added mid THF (5 ml) of was added 2H-1,2,3-triazole (0.360 mL, 6.22 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was not complete, so more 2H-1,2,3-triazole (0.300 ml, 5.18 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. Water was added and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in DCM, the solid was filtered off and the filtrate was evaporated. The residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 7/3) to give 3-chloro-5-nitro-2- (2H-1,2,3-triazole) 2-yl) pyridine was obtained. Rt = 0.75 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.39 (d, 1 H), 9.15 (d, 1 H), 8.33 (s, 2 H).

b) 5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine 3-chloro-5-nitro-2- (2H-1,2,3-triazole-2) Tin (II) chloride (2.1 g, 11.1 mmol) was added in small portions to a solution of (yl) pyridine (500 mg, 2.22 mmol) in 1.25 M HCl (35.5 ml, 44 mmol) in MeOH at room temperature . The reaction was stirred at room temperature for 2 hours. The mixture was evaporated and the residue was diluted with DCM. The mixture was basified with 1 N aqueous NaOH solution and the phases separated. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 0/1) to give 5-chloro-6- (2H-1,2,3-triazol-2-yl) Pyridine-3-amine was obtained. M / z = 196-198 [M + H] +, Rt = 0.50 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.05 (s, 2H), 7.81 (s, 1H), 7.20 (s, 1 H), 6.20 (d, 2 H).
E22: 2- (Difluoromethyl) pyridin-4-amine

a) tert-Butyl (2- (difluoromethyl) pyridin-4-yl) carbamate To a solution of 2- (difluoromethyl) isonicotinic acid (500 mg, 2.89 mmol) in tBuOH (30 ml), DPPA (0.75 ml, 3.47 mmol) was added followed by Et ₃ N (1.21 ml, 8.7 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was then stirred at 100 ° C. for 4 hours. The mixture was concentrated and the residue was dissolved in AcOEt, washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 1/1) to give tert-butyl (2- (difluoromethyl) pyridin-4-yl) carbamate. M / z = 245 [M + H] +, Rt = 0.96 min (UPLC method B1).

b) 2- (Difluoromethyl) pyridin-4-amine tert-butyl (2- (difluoromethyl) pyridin-4-yl) carbamate (125 mg, 0.51 mmol) in solution in MeOH (1 ml) 4M HCl in dioxane (2.56 ml, 10.2 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was evaporated and dried on HV to give 2- (difluoromethyl) pyridin-4-amine. M / z = 145 [M + H] +, Rt = 0.19 min (UPLC method B1).
E23: 5-chloro-6- (difluoromethoxy) pyridin-3-amine

a) 3-Chloro-2- (difluoromethoxy) -5-nitropyridine: 3-chloro-5-nitropyridin-2-ol (1.0 g, 5.73 mmol) of CH in a heat gun dried flask at room temperature under argon. _{To a} solution of ₃ CN (100 ml), 60% NaH in mineral oil (619 mg, 15.5 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 15 minutes. Then 2,2-difluoro-2- (fluorosulfonyl) -acetic acid (1.0 ml, 9.74 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0 ° C. and quenched by the dropwise addition of water (50 ml). The mixture was diluted with AcOEt and the phases separated. The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with water (3 ×), brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (n-hexane / TBME: 1/0 to 8/2) to give 3-chloro-2- (difluoromethoxy) -5-nitropyridine. Rt = 0.99 min (UPLC method B2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.11 (d, 1 H), 8. 97 (d, 1 H), 7.84 (t, 1 H).

b) 5-chloro-6- (difluoromethoxy) pyridin-3-amine 3-chloro-2- (difluoromethoxy) -5-nitropyridine (454 mg, 2.02 mmol) in AcOH (5 ml) at room temperature Iron powder (1.13 g, 20.2 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with toluene and evaporated. The residue was dissolved in DCM, filtered over a pad of celite and incorporated into DCM. The filtrate was washed with saturated aqueous NaHCO ₃ solution and the phases separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated to give 5-chloro-6- (difluoromethoxy) pyridin-3-amine. M / z = 195-197 [M + H] +, Rt = 0.82 min (UPLC method B2).
E24: 5-chloro-2- (2- (dimethylamino) ethoxy) pyridin-3-amine

a) 2-((5-Chloro-3-nitropyridin-2-yl) oxy) -N, N-dimethylethanamine 5-chloro-3-nitropyridin-2-ol (1.0 g, 5.61 mmol) , A solution of 2- (dimethylamino) ethanol (0.63 ml, 6.18 mmol) and triphenylphosphine (1.79 g, 6.74 mmol) in THF (20 ml) at 0 ° C. 18 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Then add more 2- (dimethylamino) ethanol (0.63 ml, 6.18 mmol), triphenylphosphine (1.79 g, 6.74 mmol) and DEAD (1.0 ml, 6.18 mmol) and let the reaction mixture Stir at room temperature overnight. The mixture was diluted with water and extracted three times with AcOEt. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product is purified by flash column chromatography on silica gel (heptane / AcOEt: 4/6 to 0/1) and then by preparative HPLC (method A4) to give 2-((5-chloro-3-nitro) Pyridin-2-yl) oxy) -N, N-dimethylethanamine was obtained. M / z = 246 to 248 [M + H] +, Rt = 0.47 min (UPLC method B2).

b) 5-chloro-2- (2- (dimethylamino) ethoxy) pyridin-3-amine 2-((5-chloro-3-nitropyridin-2-yl) oxy) -N, N-dimethylethanamine ( A mixture of 235 mg, 0.96 mmol) and iron (534 mg, 9.6 mmol) in EtOH (4 ml) and saturated aqueous NH ₄ Cl (1 ml) was stirred at 100 ° C. for 2 days. The mixture was filtered over a pad of celite and the filtrate was concentrated. The crude product is purified by flash column chromatography on silica gel (DCM / MeOH + 0.1% NH ₃ : 1/0 to 4/6) to give 5-chloro-2- (2- (dimethylamino) ethoxy) pyridine -3- amine was obtained. M / z = 216 to 218 [M + H] +, Rt = 0.44 min (UPLC method B2), ¹ H NMR (400 MHz, methanol-d4) δ: 7.34 (d, 1 H), 6.96 (d, 1 H) , 4.54 (m, 2H), 3.30 (m, 2H), 2.76 (s, 6H).
Part F: Synthesis of heteroaromatic acids F1: 5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) isonicotinic acid

b) Methyl 5-bromo-2- (trifluoromethyl) isonicotinate 5-bromo-2- (trifluoromethyl) isonicotinic acid (1.0 g, 3.70 mmol) in THF (5 ml) and MeOH (5 ml) To the medium solution was added trimethylsilyldiazomethane (0.85 g, 7.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (cyclohexane / EtOAc 1/0 to 8/2) to give methyl 5-bromo-2- (trifluoromethyl) isonicotinate . Rt = 1.08 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.14 (s, 1 H), 8.23 (s, 1 H), 3.93 (s, 3 H).

b) Methyl 5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) isonicotinate methyl 5-bromo-2- (trifluoromethyl) isonicotinate (200 mg, 0 .70mmol), 1H-1,2,3- triazole (65 mg, 0.92 mmol) and _Cs 2 _CO 3 (252mg, solution medium DMF (3 ml) of 0.78 mmol), and stirred for 1 hour at 60 ° C.. The reaction mixture was quenched with saturated aqueous NaHCO ₃ solution and extracted with AcOEt. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by flash column chromatography on silica gel (cyclohexane / EtOAc 1/0 to 1/1) to give methyl 5- (2H-1,2,3-triazol-2-yl) -2- (triyl). Fluoromethyl) isonicotinate was obtained. M / z = 273 [M + H] +, Rt = 1.01 min (UPLC method B1).

c) methyl 5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) isonicotinic acid 5- (2H-1,2,3-triazol-2-yl) -2 To a solution of-(trifluoromethyl) isonicotinate (75 mg, 0.276 mmol) in EtOH (3 ml) was added 2 M aqueous NaOH solution (0.15 ml, 0.30 mmol). The mixture was stirred at room temperature overnight. The reaction mixture is quenched with 1 N aqueous HCl to pH 2-3, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered and evaporated to give 5- (2H-1,2,3-triazole- 2-yl) -2- (trifluoromethyl) isonicotinic acid was obtained. M / z = 257 [M-H]-, Rt = 0.42 min (UPLC method B1).
F2: 2- (Difluoromethyl) isonicotinic acid

To a stirred solution of ethyl 2- (difluoromethyl) isonicotinate (835 mg, 4.15 mmol) in THF (5 ml) was added 2 M LiOH in water (2.59 ml, 5.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated. The residue was dissolved in 1 N aqueous HCl (pH 4) and the mixture was extracted with DCM (10 ×). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated to give 2- (difluoromethyl) isonicotinic acid. M / z = 174 [M + H] +, Rt = 0.42 min (UPLC method B2).

Example 1
(S) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

(S) -2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (380 mg, 1.49 mmol) in 1,4-dioxane (5 ml), It sealed vial DPPA (0.38ml, 1.78mmol) and _Et 3 N _(0.62ml, 4.46mmol) was added. The yellow solution was stirred at room temperature for 30 minutes. Then 6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-amine (681 mg, 2.97 mmol) is added and the reaction mixture is heated to 100 ° C. Stir for hours. After cooling to room temperature, water was added and the mixture was extracted with AcOEt, washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (DCM / MeOH: 100/0 to 80/20) and then the product is precipitated in MeOH and filtered to (S) -1- ( 6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1 5-a] pyrimidin-6-yl) urea was obtained. M / z = 482-484 [M + H] +, Rt = 4.41 min (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.46 (s, 1 H), 8.97 (s, 1 1H), 8.83 (d, 1 H), 8. 72 (d, 1 H), 8. 64 (s, 1 H), 8. 17 (s, 2 H), 6. 95 (s, 1 H), 5.43 (q, 1 H), 1. 59 (d, 3 H) ).

Example 2
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea

Solution of (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (1.3 g, 4.78 mmol) in 1,4-dioxane (10 ml) in, was added DPPA (1.24 ml, 5.74 mmol) and _{Et 3 N (3.33ml, 23.9mmol)} . The reaction mixture was stirred at room temperature for 30 minutes. Then 2- (trifluoromethyl) pyridin-4-amine (1.55 g, 9.56 mmol) was added and the reaction mixture was stirred at 100 ° C. for 2 hours. The mixture was partitioned between AcOEt and saturated aqueous NaHCO ₃ and the phases separated. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 0/1). The residue was then dissolved in MeOH and heated to dissolution. After cooling to room temperature, the precipitate is collected by filtration, washed with MeOH, dried and (S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine -6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea was obtained. M / z = 415-417 [M + H] +, Rt = 4.18 minutes (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.38 (s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H), 8.06 (d, 1H), 7.61 (dd, 1H), 6.94 (s, 1H), 5.41 (q, 1H), 3.32 (s, 3H) ), 1.57 (d, 3H).

[Example 3]
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoro) Methyl) -1,2-dihydropyridin-3-yl) urea

(S) -2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (70 mg, 0.274 mmol) in 1,4-dioxane (5 ml), DPPA (0.071ml, 0.329mmol) and _Et 3 N (0.19ml, 1.37mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Then 3-amino-1-methyl-5- (trifluoromethyl) pyridin-2 (1H) -one (52.6 mg, 0.274 mmol) was added and the reaction mixture was stirred at 100 ° C. for 2 hours. The mixture was extracted with AcOEt and saturated aqueous NaHCO ₃ solution, and the phases were separated. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 0/1). The product was then purified again by preparative HPLC (method A1), the fractions were combined and extracted with AcOEt and saturated aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered, evaporated and dried under HV to give (S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a ] Pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoromethyl) -1,2-dihydropyridin-3-yl) urea was obtained. M / z = 445-447 [M + H] +, Rt = 4.32 minutes (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.59 (s, 1 H), 9.12 (s, 1H), 8.77 (s, 1H), 8.26 (d, 1H), 8.06 (bs, 1H), 6.92 (s, 1H), 5.38 (q, 1H), 3.60 (s, 3H), 3.23 (s, 3H) ), 1.56 (d, 3H).

Example 4
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

(R) -2-Chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-carboxylic acid (70 mg, 0.165 mmol) in 1,4-dioxane (8 ml) was added a solution, under argon DPPA (0.044 ml, 0.199 mmol) and _Et 3 N _{(0.115ml, 0.827mmol)} was added. The reaction mixture was stirred at room temperature for 30 minutes. Then 6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-amine (45.5 mg, 0.199 mmol) is added and the reaction mixture is heated to 100 ° C. The mixture was stirred for 16 hours. The mixture was cooled to room temperature and more diphenylphosphoryl azide (0.044 ml, 0.199 mmol) and Et ₃ N (0.115 ml, 0.827 mmol) were added and the reaction mixture was stirred at 100 ° C. for 2.5 hours. Aqueous NaHCO ₃ solution was added and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by preparative SFC (Method A5) and the fractions are lyophilized to give (R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- ( Trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 510 to 512 [M + H] +, Rt = 5.42 (HPLC method C1), ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm: 10.54 (s, 1 H), 8. 97 (s, 1 H) ), 8.83 (d, 1 H), 8. 71 (d, 1 H), 8. 50 (s, 1 H), 8. 17 (s, 2 H), 6. 94 (s, 1 H), 5.09 (d, 1 H), 3. 36 (s, 3 H) , 2.36 (s, 1 H), 1.08 (d, 3 H), 0.81 (d, 3 H).

[Example 5]
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxy-2) -Methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

(R) -2-Chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-carboxylic acid (70 mg, 0.165 mmol) in 1,4-dioxane (8 ml) was added a solution, under argon DPPA (0.044 ml, 0.199 mmol) and _Et 3 N _{(0.115ml, 0.827mmol)} was added. The reaction mixture was stirred at room temperature for 30 minutes. Then 5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine (38.8 mg, 0.199 mmol) is added and the reaction mixture is stirred at 100 ° C. for 16 hours did. The mixture was cooled to room temperature, diphenylphosphoryl azide (0.044 ml, 0.199 mmol) and Et ₃ N (0.115 ml, 0.827 mmol) were added and the reaction mixture was stirred at 100 ° C. for 2.5 hours. The mixture was diluted with AcOEt and saturated aqueous NaHCO ₃ solution and the phases separated. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude was purified by preparative SFC (method A5) and the fractions were lyophilized. The product is purified again by preparative HPLC (method A2) and the fractions are lyophilized to give (R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) ) Pyridin-3-yl) -3- (2-chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 476 to 478 [M + H] +, Rt = 4. 70 (HPLC method C1), ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm: 10.40 (s, 1 H), 8.95 (s, 1 H) ), 8.53 (d, 1 H), 8. 49 (d, 1 H), 8.44 (s, 1 H), 8. 15 (s, 2 H), 6. 93 (s, 1 H), 5.08 (d, 1 H), 3. 35 (s, 3 H) , 2.38 (d, 1 H), 1.08 (d, 3 H), 0.81 (d, 3 H).

[Example 6]
(S) -1- (7- (1-Methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea

(S) -7- (1-Methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid (100 mg, 0.425 mmol) in solution in 1,4-dioxane (5 ml) DPPA (0.110 mL, 0.510 mmol) and _Et 3 N _(0.296ml, 2.13mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Then 2- (trifluoromethyl) pyridin-4-amine (138 mg, 0.850 mmol) was added and the reaction mixture was stirred at 100 ° C. overnight. AcOEt and saturated aqueous NaHCO ₃ were added and the phases separated. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 0/1). The product is then purified again by preparative HPLC (method A1), the fractions are combined, extracted with AcOEt and saturated aqueous NaHCO ₃ solution, the organic layer is dried over Na ₂ SO ₄ , filtered and evaporated, over HV (S) -1- (7- (1-methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine- 4-yl) urea was obtained. M / z = 395 [M + H] +, Rt = 3.54 min (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.31 (s, 1H), 8.74 (s, 1H) , 8.55 (d, 1 H), 8.43 (s, 1 H), 8.06 (d, 1 H), 7.61 (dd, 1 H), 6.56 (s, 1 H), 5. 50 (q, 1 H), 3. 30 (s, 3 H), 2.44 (s, 3H), 1.56 (d, 3H).

[Example 7]
(S) -1- (2-Fluoro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea

(S) -2-Fluoro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (140 mg, 0.556 mmol) in 1,4-dioxane (3 ml), under argon DPPA (0.144ml, 0.667mmol) and _Et 3 N (0.23ml, _1.67mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Then 2- (trifluoromethyl) pyridin-4-amine (135 mg, 0.834 mmol) was added and the reaction mixture was stirred at 100 ° C. overnight. The mixture was extracted with AcOEt and brine. The organic layer was dried on a phase separation cartridge (IST) and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 1/9). The product was dissolved in hot MeOH and after cooling to room temperature, the mixture was centrifuged and the mother liquor was removed to give a solid. The product is then further purified by preparative HPLC (method A1), the fractions are combined, extracted with DCM and saturated aqueous NaHCO ₃ solution, the organic phase is dried on a phase separation cartridge (IST) and evaporated, on HV Dried to give (S) -1- (7- (1-methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine-4 Yl) urea was obtained. M / z = 399 [M + H] +, Rt = 3.90 minutes (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.34 (bs, 1H), 8.87 (s, 1H) , 8.56 (d, 1 H), 8.53 (bs, 1 H), 8.06 (s, 1 H), 7.61 (d, 1 H), 6. 57 (d, 1 H), 5.32 (q, 1 H), 3.30 (s, 3 H), 1.56 (d, 3H).

[Example 8]
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-cyanopyridin-3-yl) urea

A solution of (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid (50 mg, 0.19 mmol) in 1,4-dioxane (0.8 ml) in, was added DPPA (0.051 ml, 0.228 mmol) and _{Et 3 N (0.079ml, 0.569mmol)} . The reaction mixture was stirred at room temperature for 30 minutes. Then 5-aminonicotinonitrile (67.8 mg, 0.569 mmol) was added and the reaction mixture was stirred at 100 ° C. for 30 minutes. The mixture was evaporated and the residue was dissolved in AcOEt. The organic layer was washed with saturated aqueous NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt: 1/0 to 0/1) to give (S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [ 1,5-a] pyrimidin-6-yl) -3- (5-cyanopyridin-3-yl) urea was obtained. M / z = 372-374 [M + H] +, Rt = 3.18 min (HPLC method C1), ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm: 10.09 (s, 1 H), 8. 92 (s, 1H), 8.83 (d, 1H), 8.64 (d, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 6.92 (s, 1H), 5.41 (q, 1H), 3.30 (s, 3H) ), 1.57 (d, 3H).

  As in Example 1, the following examples were prepared:

[Example 112]
1- (5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) pyridin-4-yl) -3- (2-chloro-7-isopropylpyrazolo [1,1] 5-a] pyrimidin-6-yl) urea

a) tert-Butyl (2-chloro-7-isopropyl pyrazolo [1,5-a] pyrimidin-6-yl) carbamate 2-chloro-7-isopropyl pyrazolo [1,5-a] pyrimidine-6-carboxylic acid acid (200 mg, 0.835 mmol) to a solution medium tBuOH (5 ml) of was added DPPA (0.198ml, 0.918mmol) and _{Et 3 N (0.58ml, 4.17mmol)} . The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then stirred at 100 ° C. for 3 hours. The solvent is evaporated and the crude product is purified by flash column chromatography on silica gel (cyclohexane / EtOAc: 1/0 to 1/1) to give tert-butyl (2-chloro-7-isopropylpyrazolo [1 5-a] pyrimidin-6-yl) carbamate was obtained. M / z = 311 to 313 [M + H] +, Rt = 1.22 minutes (UPLC method B1).

b) 2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-amine tert-butyl (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) carbamate A solution of (90 mg, 0.290 mmol) and 4N HCl in 1,4-dioxane (0.36 ml, 1.45 mmol) in methanol (3 ml) was stirred at room temperature overnight. The reaction mixture is concentrated, quenched with saturated aqueous NaHCO ₃ solution, extracted with AcOEt, the organic phase is dried over Na ₂ SO ₄ , filtered and concentrated to give 2-chloro-7-isopropylpyrazolo [1,5 -A] Pyrimidin-6-amine was obtained. M / z = 211-213 [M + H] +, Rt = 0.87 min (UPLC method B1).

c) 1- (5- (2H-1,2,3-Triazol-2-yl) -2- (trifluoromethyl) pyridin-4-yl) -3- (2-chloro-7-isopropylpyrazolo [ 1,5-a] Pyrimidin-6-yl) urea 5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) isonicotinic acid (60 mg, 0.232 mmol) 1 , 4 to a solution in dioxane (3 ml), was added DPPA (0.060 ml, 0.279 mmol) and _{Et 3 N (0.065ml, 0.465mmol)} . The mixture was stirred at room temperature for 30 minutes. Then 2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-amine (58.8 mg, 0.279 mmol) was added and the reaction mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was extracted with AcOEt, and the organic phase was washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (cyclohexane / EtOAc 1/0 to 0/1 then DCM / MeOH 1/0 to 9/1). The resulting residue was purified twice by preparative HPLC (method A1). The fractions containing product were extracted with AcOEt / saturated aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered and evaporated to give 1- (5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) pyridine-4- Yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 466 to 468 [M + H] +, Rt = 2.45 min (HPLC method C2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.00 (bs, 1 H), 9.16 (s, 1H), 8.97 (s, 1 H), 8. 57 (s, 1 H), 8.41 (s, 1 H), 6. 94 (s, 1 H), 3. 79 (seven wire, 1 H), 1. 48 (d, 6 H).

[Example 113]
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Hydroxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (7- (1- (benzyloxy) A solution of (ethyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) urea (20 mg, 0.036 mmol) and palladium Perlman's catalyst (0.50 mg, 3.58 μmol) in AcOEt (2 ml) Stir at room temperature under H ₂ atmosphere overnight. The reaction mixture was filtered and concentrated. The residue is purified by preparative HPLC (method A1) to give (R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridine-3 Y-yl) -3- (2-chloro-7- (1-hydroxyethyl) -pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 468 to 470 [M + H] +, Rt = 3.90 minutes (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.68 (s, 1 H), 9.04 (s, 1H), 8.85 (d, 1H), 8.74 (d, 1H), 8.18 (d, 2H), 6.93 (s, 1H), 5.79 (q, 1H), 1.56 (d, 3H).

[Example 114]
(S) -1- (2-Chloro-7- (1-hydroxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea

a) (S) -1- (7- (1- (1- (benzyloxy) ethyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoro-methyl) pyridine -4-yl) urea (S) -7- (1- (benzyloxy) ethyl) -2-chloropyrazolo [1,5-a] pyrimidine-6-carboxylic acid (500 mg, 1.34 mmol) in dioxane (3 ml) To the medium solution diphenylphosphoryl azide (443 mg, 1.61 mmol) and triethylamine (0.56 ml, 4.02 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Then 2- (trifluoromethyl) pyridin-4-amine (435 mg, 2.68 mmol) was added and the solution was stirred at 100 ° C. for 1.5 hours. After cooling, the reaction mixture was extracted with EtOAc, washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by flash column chromatography on silica gel (cyclohexane / EtOAc: 100/0 to 0/100) to give (S) -1- (7- (1- (benzyloxy) ethyl) -2-) Chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea was obtained. M / z = 491~493 [M + H] +, Rt = 1.31 min (UPLC method ^{B1), 1 H NMR (400} MHz, DMSO-d 6) δ ppm: 10.18 (s, 1H), 8.81 (s, 1H), 8.55 (d, 1H), 8.52 (s, 1H), 8.01 (d, 1H), 7.58-7.54 (m, 1H), 7.29-7.20 (m, 2H), 7.15-7.08 (m, 3H) , 6.91 (s, 1 H), 5.56 (q, 1 H), 4.51 (q, 2 H), 1.62 (s, 3 H).

b) (S) -1- (2-chloro-7- (1-hydroxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine-4-) (I)) Urea (S) -1- (7- (1- (1- (benzyloxy) ethyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine A solution of 4-yl) urea (140 mg, 0.285 mmol) and palladium-Pearlman's catalyst (4.0 mg, 29 μmol) in THF (5 ml) was stirred at room temperature overnight under an atmosphere of H ₂ . The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (method A1). EtOAc and aqueous NaHCO ₃ were added to the fractions containing the product. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH 1/0 to 8/2) to give ((S) -1- (2-chloro-7- (1-hydroxyethyl) pyrazolo [1 5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea was obtained M / z = 401 to 403 [M + H] +, Rt = 0.99. Minutes (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.55 (s, 1 H), 8. 98 (s, 1 H), 8. 94 (s, 1 H), 8.56 (d, 1 H), 8.07 (s, 1 H), 7.61 (d, 1 H), 6. 91 (s, 1 H), 6. 77-6. 61 (m, 1 H), 5. 76 (q, 1 H), 1.52 (d, 3 H).

[Example 115]
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-2-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea

Tert-Butyl 2- (2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridine) dissolved in DCM (0.27 ml) To (yl) ureido) pyrazolo [1,5-a] pyrimidin-7-yl) morpholine-4-carboxylate (124 mg, 0.082 mmol), TFA (63.1 [mu] l, 0.819 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and the separated aqueous phase was basified to pH = 8-9 with saturated aqueous NaHCO ₃ solution and extracted with DCM. The organic phase was washed with brine, dried on a phase separation cartridge (IST) and evaporated. The residue was purified by preparative HPLC (method A1). The collected fractions were extracted with DCM / saturated aqueous NaHCO ₃ solution. The organic phase is dried on a phase separation cartridge (IST) and concentrated to give 1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3-3. (2-Chloro-7- (morpholin-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 475 to 477 [M + H] +, Rt = 1.46 min (HPLC method C2), ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm: 8.90 (s, 1 H), 8.45 (d, 1H), 8.43 (d, 1 H), 7. 92 (s, 2 H), 6. 59 (s, 1 H), 5.63 (dd, 1 H), 4. 10 (dd, 1 H), 3. 76 (td, 1 H), 3.07-2.76 (m , 4H).

[Example 116]
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methylmorpholin-2-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea

1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-2-yl) pyrazolo [1 Acetic acid (2.70 μl, 0.047 mmol) and 37% aqueous formaldehyde (5.26 μl, 0. 1) were added to a solution of 5-a] pyrimidin-6-yl) urea (14 mg, 0.024 mmol) in MeOH (236 μl). 071 mmol) was added. After 30 minutes, NaBH (OAc) ₃ (15.0 mg, 0.071 mmol) was added at 0 ° C. and the reaction mixture was stirred at room temperature for 1 hour. Water was carefully added and the solvent was evaporated. The residue was purified by preparative HPLC (method A1). The collected fractions were extracted with DCM / saturated aqueous NaHCO ₃ solution. The organic phase is dried on a phase separation cartridge (IST) and concentrated to give 1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3-3. (2-Chloro-7- (4-methylmorpholin-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 489 to 491 [M + H] +, Rt = 1.48 min (HPLC method C2), ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm: 8.91 (s, 1 H), 8.44 (d, 1H), 8.42 (d, 1H), 7.92 (s, 2H), 6.59 (s, 1H), 5.69 (dd, 1H), 4.13 (ddd, 1H), 3.81 (td, 1H), 3.07 (dt, 1H) 2.76 (ddt, 1H), 2.33 (td, 1H), 2.27 (s, 3H), 2.23 (dd, 1H).
[Example 117]
1- (4- (4- (aminomethyl) -1H-pyrazol-1-yl) -3-chlorophenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6- Il) urea

a) tert-Butyl ((1- (2-chloro-4- (3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) ureido) phenyl) -1H-pyrazole -4-yl) methyl) carbamate 2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1 5-a] pyrimidine-6-carboxylic acid is used in place of tert-butyl ((1- (4-amino-2-chlorophenyl) -1H-pyrazol-4-yl) methyl) carbamate as 6- (2H- As a substitute for 1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-amine, as described in Example 1, tert-butyl ((1- (2-chloro) Preparation of lo-4- (3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) ureido) phenyl) -1H-pyrazol-4-yl) methyl) carbamate similarly did. M / z = 559-561 [M + H] +, Rt = 1.17 min (UPLC method B2).

b) 1- (4- (4- (aminomethyl) -1H-pyrazol-1-yl) -3-chlorophenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine- 6-yl) urea tert-butyl ((1- (2-chloro-4- (3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) in DCM (2 ml) To the (Ureido) phenyl) -1H-pyrazol-4-yl) methyl) carbamate (86 mg, 0.154 mmol) was added TFA (1 ml, 12.98 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent is evaporated and the residue is purified by preparative HPLC (method A1) to give 1- (4- (4- (aminomethyl) -1H-pyrazol-1-yl) -3-chlorophenyl) -3- ( 2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 459-461 [M + H] +, Rt = 3.09 minutes (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.55 (s, 1 H), 7.88 (d, 2H), 7.64 (s, 1H), 7.49 (dd, 1H), 7.45 (d, 1H), 6.92 (d, 1H), 3.81 (p, 1H), 3.67 (s, 2H), 1.50 (d, 6H) ).

[Example 118]
1- (6- (4- (aminomethyl) -1H-pyrazol-1-yl) -5-chloropyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a ] Pyrimidin-6-yl) Urea

tert-Butyl ((1- (5-amino-3-chloropyridin-2-yl) -1H-pyrazol-4-yl) methyl) carbamate to tert-butyl ((1- (4-amino-2-chlorophenyl)) 1- (6- (4- (aminomethyl) -1H-pyrazol-1-yl) -5, as described in Example 117, for the substitution of (-1H-pyrazol-4-yl) methyl) carbamate -Chloropyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea was prepared analogously. M / z = 460-462 [M + H] +, Rt = 2.97 minutes (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.56 (s, 1 H), 8.52 (d, 1H), 8.34 (d, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 6.93 (s, 1H), 3.82 (p, 1H), 3.69 (s, 2H), 1.50 (d, 6H) ).

[Example 119]
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

a) (S) -tert-butyl (1- (2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) Ureido) pyrazolo [1,5-a] pyrimidin-7-yl) ethyl) (methyl) carbamate (S) -7- (1-((tert-butoxycarbonyl) (methyl) amino) ethyl) -2-chloropyrazolo [ 1, 5-a] pyrimidine-6-carboxylic acid is used in place of (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1, 5-a] pyrimidine-6- carboxylic acid; Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine 6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) Used in place of pyridin-3-amine , As described in Example 1, (S) -tert-butyl (1- (2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazole-2-) Yl) pyridin-3-yl) ureido) pyrazolo [1,5-a] pyrimidin-7-yl) ethyl) (methyl) carbamate was prepared analogously. M / z = 547 to 549 [M + H] +, Rt = 1.28 min (UPLC method B1).

b) (S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (1-) (Methylamino) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea (S) -tert-butyl (1- (2-chloro-6- (3- (5-chloro-6- (2H-) 1,2,3-Triazol-2-yl) pyridin-3-yl) ureido) pyrazolo [1,5-a] pyrimidin-7-yl) ethyl) (methyl) carbamate (215 mg, 0.393 mmol) in MeOH To a solution in 3 ml) was added 4N HCl in 1,4-dioxane (0.098 ml, 0.393 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, treated with AcOEt / saturated aqueous NaHCO ₃ solution, the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 0/1 then DCM / MeOH 1/0 to 8/2) to give 1- (5-chloro-6- (2H-) 1,2,3-Triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methylamino) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl ) Obtained urea. Chiral analysis indicated that some racemization had occurred during the synthesis.

The mixture of enantiomers is separated by preparative chiral separation (Chiralpak aD-H, 250 × 4.6 mm, 5 μm, heptane / EtOH / MeOH 60/20/20, 1 mL / min) to give (S) -1- (5-) Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methylamino) ethyl) pyrazolo [1,5- a] Pyrimidin-6-yl) urea was obtained. M / z = 447 to 449 [M + H] +, Rt = 2.42 min (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.34 (s, 1 H), 9.05 (s, 1H), 8.60 (d, 1H), 8.50 (d, 1H), 8.17 (s, 2H), 6.91 (s, 1H), 4.75 (q, 1H), 2.28 (s, 3H), 1.49 (d, 3H) ).

[Example 120]
2- (3- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) ureido) -4- (trifluoromethyl) pyridine 1-oxide

a) 1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (4- (trifluoromethyl) pyridin-2-yl) urea 2-chloro-7 -Isopropylpyrazolo [1,5-a] pyrimidine-6-carboxylic acid instead of (S) -2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6-carboxylic acid Use 4- (trifluoromethyl) pyridin-2-amine instead of 6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-amine 1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (4- (trifluoromethyl) pyridine-2-, as described in Example 1 Yl) urea was similarly prepared . M / z = 399-401 [M + H] +, Rt = 1.19 min (UPLC method B2).

b) 2- (3- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) ureido) -4- (trifluoromethyl) pyridine 1-oxide 1- (2-chloro) -7-Isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (4- (trifluoromethyl) pyridin-2-yl) urea (40 mg, 0.100 mmol) in DCM (1 ml) To the stirring solution, mCPBA (17.31 mg, 0.100 mmol) was carefully added and the reaction mixture was stirred at room temperature overnight. mCPBA (6.92 mg, 0.040 mmol) was added again and the reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness under vacuum and the residue was purified by preparative HPLC (method A1). The fractions were basified with saturated aqueous NaHCO ₃ solution and extracted with DCM. The organic phase is dried on a phase separation cartridge (IST) and concentrated to give 2- (3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) ureido) -4- (Trifluoromethyl) pyridine 1-oxide was obtained. M / z = 413 to 415 [M + H] +, Rt = 2.14 minutes (HPLC method C2), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.58 (s, 1 H), 9.64 (s, 1H), 8.63 (s, 1H), 8.61 (s, 1H), 8.55 (d, 1H), 7.46 (dd, 1H), 6.93 (s, 1H), 3.85 (p, 1H), 1.49 (d, 6H) ).

[Example 121]
(R) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methylamino) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea (329mg, 0.736mmol) (the solution medium DMF (6 ml) of the obtained) as described in example _{119, K 2 CO 3 (203mg} , 1.471 mmol) was added, then a solution of iodomethane (0.046 ml, 0.736 mmol) in DMF (1 ml) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. More iodomethane (0.015 ml, 0.245 mmol) was added and the mixture was stirred for 15 minutes. The reaction mixture was concentrated and extracted with AcOEt, the organic phase was washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 0/1 then DCM / MeOH 1/0 to 8/2) to give a mixture of enantiomers. A mixture of both isomers is separated by preparative chiral separation (Chiralpak IC, 250 × 4.6 mm, 5 μm, heptane / EtOH 60/40 + 0.05% diethylamine, 1 ml / min) to (R) -1- (5) -Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ethyl) pyrazolo [1,5 -A] Pyrimidin-6-yl) urea was obtained. M / z = 461-463 [M + H] +, Rt = 0.67 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.48 (s, 1 H), 10.18 (s, 1H), 9.10 (s, 1H), 8.60 (d, 1H), 8.51 (d, 1H), 8.17 (s, 2H), 6.91 (s, 1H), 4.46 (q, 1H), 2.34 (s, 6H) ), 1.43 (d, 3H).

[Example 122]
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

The mixture of both isomers was purified by preparative chiral separation (Chiralpak IC, 250 × 4.6 mm, 5 μm, heptane / EtOH 60/40 + 0.05% diethylamine, 1 ml / min) as described in Example 121. (S) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethyl) Amino) ethyl) -pyrazolo- [1,5-a] pyrimidin-6-yl) urea was prepared to give (S) -1- (5-chloro-6- (2H-1,2,3-triazole) 2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 461 to 463 [M + H] +, Rt = 0.68 min (UPLC method B1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.49 (s, 1H), 10.18 (s, 1H), 9.10 (s, 1H), 8.60 (d, 1H), 8.51 (d, 1H), 8.17 (s, 2H), 6.91 (s, 1H), 4.46 (q, 1H), 2.34 (s, 6H) ), 1.43 (d, 3H).

[Example 123]
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-3-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea

a) tert-Butyl 3- (2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ureido) pyrazolo [1 5-a] Pyrimidin-7-yl) morpholine-4-carboxylate 7- (4- (tert-butoxycarbonyl) morpholin-3-yl) -2-chloropyrazolo [1,5-a] pyrimidin-6-carboxylic acid A mixture of acid (289 mg, 0.755 mmol) in 1,4-dioxane (2.5 ml), DPPA (0.195 ml, 0.906 mmol) at room temperature under argon, followed by Et ₃ N (0.32 ml, 2 .26 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. Then 5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-amine (222 mg, 1.13 mmol) was added and the reaction mixture was stirred at 100 ° C. for 2 hours. The mixture was diluted with AcOEt and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt 1/0 to 0/1) to give tert-butyl 3- (2-chloro-6- (3- (5-chloro-6- ( 2H-1,2,3-Triazol-2-yl) pyridin-3-yl) ureido) pyrazolo [1,5-a] pyrimidin-7-yl) morpholine-4-carboxylate was obtained. M / z = 575 to 577 [M + H] +, Rt = 1. 11 min (UPLC method B2).

b) 1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-3-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea tert-butyl 3- (2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) )) Pyridin-3-yl) ureido) pyrazolo [1,5-a] pyrimidin-7-yl) morpholine-4-carboxylate (163 mg, 0.283 mmol) in 1,4-dioxane (2 ml) at room temperature Was added 4M HCl in 1,4-dioxane (0.71 ml, 2.83 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched at 0 ° C. with saturated aqueous NaHCO ₃ solution and extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 0/1) and then purified again by preparative HPLC (method A1). The fractions were combined and extracted with saturated aqueous NaHCO ₃ solution and DCM. The organic phase is dried on a phase separation cartridge (IST), evaporated and dried on HV to give 1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridine-3 Y-yl) -3- (2-chloro-7- (morpholin-3-yl) pyrazolo [l, 5-a] pyrimidin-6-yl) urea was obtained. M / z = 475 to 477 [M + H] +, Rt = 2.53 min (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.54 (bs, 1H), 9.02 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.15 (s, 2H), 6.89 (s, 1H), 5.05 (d, 1H), 3.87 (d, 2H), 3.65 (t, 1H) ), 3.54 (t, 1 H), 3.02 (d, 1 H), 2. 92 (t, 1 H), the two NHs are unclear due to water.

[Example 124]
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methyl-1) -(Methylamino) propyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

In step a), (S) -7- (1-((tert-butoxycarbonyl) (methyl) amino) -2-methylpropyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-carboxylic acid is used. 1- (4- (tert-butoxycarbonyl) morpholin-3-yl) -2-chloropyrazolo [1,5-a] pyrimidin-6-carboxylic acid, as described in Example 119, in place of 5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methyl-1- (methylamino) propyl) -Pyrazolo [1,5-a] pyrimidin-6-yl) urea was prepared analogously. The mixture in step a) was stirred at 100 ° C. overnight and in step b) for 2.5 hours. M / z = 475 to 477 [M + H] +, Rt = 2.77 min (HPLC method C1), 1 H NMR (400 MHz, CDCl ₃ ) δ ppm: 11.03 (bs, 1H), 9.23 (s, 1H), 8.59 (s, 1 H), 8. 37 (s, 1 H), 7. 94 (s, 2 H), 6. 87 (bs, 1 H), 6. 64 (s, 1 H), 4.81 (d, 1 H), 2. 45 (s, 3 H), 2. 34 (Seven wire, 1H), 1.09 (d, 3H), 0.99 (d, 3H).

[Example 125]
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methylmorpholin-3-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea

1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-3-yl) pyrazolo [1 To a solution of 5-a] pyrimidin-6-yl) urea (50 mg, 0.105 mmol) in THF (1.5 ml), triphenylphosphine (55.2 mg, 0.21 mmol), diisopropyl azodicarboxylate (0 .041 ml, 0.21 mmol) and then methyl iodide (0.013 ml, 0.21 mmol) were added. The reaction mixture was stirred at room temperature overnight. The mixture was evaporated. The residue is purified by flash column chromatography on silica gel (cyclohexane / AcOEt1 / 0 to 35/65). The product was triturated in MeOH, kept at room temperature for 1 h and centrifuged. The supernatant is removed and the solid product is dried on HV to give 1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-Chloro-7- (4-methylmorpholin-3-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 489 to 491 [M + H] +, Rt = 2.59 min (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.51 (bs, 1H), 9.95 (bs, 1H), 9.07 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.16 (s, 2H), 6.91 (s, 1H), 4.50 (d, 1H), 3.94 (d, 1H) ), 3.88 (d, 1 H), 3.72 (t, 1 H), 3.50 (t, 1 H), 3.03 (d, 1 H), 2.42 (m, 1 H), 2.23 (s, 3 H).

[Example 126]
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxy) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

By purifying the mixture of both enantiomers by preparative chiral separation (Chiralcel OJ-H, 10 × 50 cm, 20 μm, n-heptane / (EtOH / MeOH 1/1) 85/15 to 7/3, 1 ml / min) , (R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-) Dimethoxyethyl) pyrazolo- [1,5-a] pyrimidin-6-yl) urea was obtained. The product was suspended in cold CH ₃ CN (1.4 ml) and water (0.14 ml) and the mixture was heated to 100 ° C. until completely dissolved, then cooled to room temperature and maintained in the refrigerator over the weekend. The solid was filtered off and dried on HV to give a pure product. M / z = 478-480 [M + H] +, Rt = 4.01 min (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.43 (bs, 1H), 8.94 (s, 1H), 8.55 (m, 1H), 8.49 (m, 2H), 8.15 (s, 2H), 6.95 (s, 1H), 5.51 (m, 1H), 3.85 (m, 2H), 3.36 (s, 3H) ), 3.29 (s, 3H).

[Example 127]
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxy) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea

Purification of the mixture of both isomers by preparative chiral separation (Chiralcel OJ-H, 10 × 50 cm, 20 μm, n-heptane / (EtOH / MeOH 1/1) 85/15 to 7/3, 1 ml / min) (S) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2) -Dimethoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea was obtained. M / z = 478-480 [M + H] +, Rt = 4.00 minutes (HPLC method C1), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.41 (bs, 1H), 8.95 (s, 1H), 8.55 (m, 1H), 8.49 (m, 1H), 8.47 (bs, 1H), 8.16 (s, 2H), 6.95 (s, 1H), 5.50 (m, 1H), 3.84 (m, 2H) ), 3.36 (s, 3 H), 3. 29 (s, 3 H).

Biological / pharmacologic items The compounds of the present invention have valuable pharmacological properties, eg as shown in the test assay presented below, eg, a sensitive property for MALT1, eg a protein of MALT1 It exhibits inhibition of degradation activity and / or autoproteolytic activity and is therefore indicated for treatment.

Assay:
Biochemical assay for MALT1:
The IC50 values of the test compounds were determined using an enzyme activity assay using the C-domain of MALT1 (amino acids 329-824). The readout parameter is the improvement of fluorescence lifetime over time, which is proportional to the enzyme activity.

This assay is sensitive to the cleavage state of the substrate (PT14: 6- (9-oxo-9H-acridin-10-yl) -hexanoate, AssayMetrics, UK), labeled with a single fluorophore PT14 as a fluorescence lifetime probe The short chain peptide substrate is used. The peptide substrate has the following sequence: Ac-Trp-Leu-Arg-Ser-Arg ^ Cys (PT14) -NH ₂ (Product No. BS-9117, Biosyntan, Germany, N-terminal from left to right in the three letter code Ac residue to C-terminus, Ac: acetyl group, Cys (PT14): cysteine residue having fluorophore PT14 conjugated to cysteine sulfhydryl group via maleimide group; C-terminus of this peptide is amidated In the range of the above-mentioned substrate sequence, ^ indicates a bond that is susceptible to cleavage. The assay buffer consists of 200 mM Tris / HCl, pH 7.5, 0.8 M Na citrate, 100 μM EGTA, 100 μM DTT and 0.05% (w / v) CHAPS. The kinetic characteristics of the enzyme reaction determined the Michaelis constant (K _M ) 40 μM and the kcat value 34 s ⁻¹ . This assay was established for the 384-well plate format using black microtiter round well plates (Product no. 95040020, Thermo Electron Oy, Finland). The test compounds were dissolved in 100% (v / v) DMSO, or a mixture containing 100 mM stock concentrations of 90% (v / v) DMSO and 10% (v / v) H 2 O. Serial dilutions of test compounds are prepared using either 100% (v / v) DMSO or a mixture containing 90% (v / v) DMSO and 10% (v / v) H 2 O. did.

For measurement of compound inhibition, 0.25 μl of test compound was mixed with 12.5 μl of enzyme in the wells of a 384-well plate and incubated for 60 minutes at room temperature (22 ° C.). Then, 12.5 μl of substrate was added and the enzyme reaction was allowed to proceed for 60 minutes at room temperature (22 ° C.). The total assay volume was 25.25 μl, and the final assay concentrations of enzyme and substrate were 2.5 nM and 1 μM, respectively. The increase in assay signal over time is linear under reported assay conditions for at least 60 minutes and is directly proportional to the concentration of active enzyme up to at least 2.5 nM. The DMSO content was between 0.9 and 1% (v / v). The final assay concentration of test compound was typically in the range of 100 μM to 1 nM in a serial dilution series using a dilution factor of 3.16 (ie half log dilution step). As a control, in multiple wells, instead of the test compound, addition of DMSO alone results in an uninhibited enzymatic reaction (ie 0% inhibition) or a completely inhibited reaction (ie The reaction was performed by either adding enzyme free assay buffer mixed with DMSO, equivalent to 100% inhibition). The fluorescence lifetime was recorded using a microtiter plate reader such as the TECAN Ultra Evolution FLT instrument, with a fluorescence excitation at 405 nm and an emission record at 450 nm. Fluorescence lifetimes can be converted to percent inhibition using the above controls as a basis (0 and 100% inhibition). IC 50 values were calculated from plots of percent inhibition versus inhibitor concentration using non-linear regression analysis software (Origin, Origin Lab Corporation, USA). These data have the following formula:
y = A2 + (A1-A2) / (1+ (x / IC50) ^ p)
Where y is the percent inhibition at inhibitor concentration x, A1 is the lowest inhibition value, A2 is the highest inhibition value, and the index p is the Hill coefficient), Fit using a four parameter logistic model.

CIAP2-MALT1 driven NF kappa B reporter gene assay (RGA) in HEK 293
The fusion protein cIAP2-MALT1 drives constitutive NF-kB activation in the MALT type of B cell lymphoma. To monitor the activity of MALT1 inhibitors on NF-kB signaling, the activated cIAP2-MALT1 fusion protein is constitutively expressed and the firefly luciferase reporter gene is under the control of the NF-kB response element A mechanistic model consisting of one stably transfected HEK 293 cell line was established. Inhibition of luciferase gene expression is measured using a luciferase activity detection assay. Briefly, 1.8 x 10 ^ 4 cells / 90 ul / well are seeded in sterile white-walled, clear-bottomed 96-well microplates (Costar, catalog no. 3903) treated with tissue culture. After overnight incubation at 37 ° C., 10 μL of a 10 × 3-fold serial dilution of the compound initially prepared in DMSO, and then an intermediate dilution of 1: 100 in cell culture medium are used as liquid handling robotics (Velocity Bravo 11. Add to the above cells using Agilent). Unless stated otherwise, the starting concentration of compound is 10 μM and the final vehicle concentration is 0.1% DMSO in all wells. After 24 hours of compound incubation, cell viability was determined by adding 10 μl of 135 μg / ml resazurin sodium salt (SIGMA catalog number R7017) dissolved in phosphate buffer saline followed by 3 of the first steps Evaluate by time. Following the quantification of the reduction of resazurin at an excitation / emission wavelength of 540/590 nm on a multi-purpose microplate reader (eg Infinite M200Pro, TECAN), using 70 μL of ONEGlow (Promega, Catalog No. E6120) homogeneous assay buffer Cells are quantitated for luciferase expression levels after incubation for 20 minutes at room temperature. Luminescence is recorded on a multipurpose microplate reader (eg, Infinite M200Pro, TECAN) in fluorescence detection mode. Raw data is processed using an Excel analysis template. The effect of a particular test compound concentration on NF-kB activity is expressed as luciferase signal (relative light units) normalized to cell viability by dividing by the reduced signal of resazurin (relative fluorescence units). The values obtained for vehicle treated cells are set as 100%. Absolute (50% reduction to vehicle control) and relative (inflection point) IC50 values (μM) are determined using 4 parametric curve fitting (XLfit, V4.3.2). In addition, NF-kB signal normalized to%, and% cell viability at the highest compound concentration are tested.

Human IL2 promoter reporter gene assay (RGA) in Jurkat cells
Transfected Jurkat clone K22 290 H23 was grown in RPMI 1640 supplemented with 10% heat inactivated fetal bovine serum, 50 μM 2-mercaptoethanol and 1 mg / ml geneticin. Cell concentration should not exceed 1x10e6 / ml during culture. The cells should not exceed passage 30. Prior to the assay, cells were washed and adjusted to a concentration of 2 × 10e6 cells / ml.

Compound dilutions were performed as 2 × concentrated solutions and then diluted by half by adding to cells. 250 μl of compound dilution and 250 μl of cells were mixed together in the wells of a 96 deep well plate. The cell / compound premix was incubated for 30 minutes at 37 ° C. and 5% CO 2 directly in the deep well plate.
After preincubating cells with compounds, cells were stimulated with 3 μg / ml anti-CD28 mAb (clone 15E8) and 1 μg / ml PMA. Both costimulatory agents were diluted in culture medium at 10 × concentrated solution. 10 μl of costimulatory agent was pipetted into a white 96 well plate and 100 μl of cell / compound mix was immediately added in duplicate. The cells were stimulated for 5.5 hours at 37 ° C. and 5% CO 2.
After cell stimulation, 50 μl of BriteLite Plus reagent (Perkin Elmer) was added to each well and bioluminescence was measured by a Wallac EnVision reader (Perkin Elmer).

The following IC ₅₀ was determined using the above assay.

Utility According to the results obtained in the test assay presented above, the compounds of the invention are
Diseases or disorders selected from conditions and disorders characterized by dysregulated NF-kB activation, in particular, autoimmune / immunological and inflammatory diseases, allergic disorders, respiratory disorders and oncological disorders (indications) It is intended to be useful in the treatment of

  The autoimmune and inflammatory disorders include arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, rheumatic fever, gout , Organ or transplant rejection, acute or chronic graft versus host disease, chronic allograft rejection, Behcet's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis Inflammation, Sjögren's syndrome, and vesicosis (eg, pemphigus vulgaris), antibody-mediated vasculitis syndrome (ANCA-related vasculitis), Henoch-Schoenlein purpura and immune complex vasculitis (infection or cancer) It can be chosen among others, either primary or secondary.

  Said oncological disorders include carcinomas, sarcomas, lymphomas, leukemias and germ cell tumors such as adenocarcinoma, bladder cancer, clear cell carcinoma, skin cancer, brain cancer, cervical cancer, colon cancer, colon cancer Endometrial cancer, bladder cancer, brain cancer, breast cancer, stomach cancer, germ cell tumor, glioblastoma, liver adenoma, Hodgkin's lymphoma, liver cancer, kidney cancer, lung cancer, ovarian cancer, skin tumor, prostate Cancer, renal cell carcinoma, gastric cancer, medulloblastoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, cutaneous T cell lymphoma, melanoma, mucosa-associated lymphoid tissue (MALT ) Lymphoma, multiple myeloma, plasma cell neoplasms, malignant melanoma, and terminal melonoid melanoma can be selected among others.

  Said allergic disorders can be selected in particular from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, beryllium lung. The respiratory disorder may be asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, queiosis, pulmonary fibrosis, respiratory failure, acute respiratory distress Among the syndromes, primary pulmonary hypertension and emphysema.

  In another embodiment, the compound of the present invention is rheumatoid arthritis, systemic lupus erythematosus, vasculitis state, allergic disease, asthma, chronic obstructive pulmonary disease (COPD), acute or chronic transplant rejection, graft versus host disease, It may be useful in treating cancers or solid tumors of hematopoietic origin, chronic myelogenous leukemia, myelogenous leukemia, non-Hodgkin's lymphoma or other B cell lymphomas.

  In another embodiment, the compound of the present invention is ABC having an active mutation in BENTA disease, beryllium lung, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, polymyositis, psoriasis, eg, Card 11, MALT lymphoma -May be useful in the treatment of DLBCL.

Combinations The compounds of the invention may be administered concurrently with, or either before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.

  The compounds according to the invention can be used as sole active ingredient or, alternatively, as an adjuvant, another drug, for example for the treatment or prophylaxis of acute or chronic rejection or inflammation of autografts or xenografts, or autoimmune disorders. For example, it can be administered in combination with an immunoregulator or immunomodulator or other anti-inflammatory agent, or a chemotherapeutic agent such as a malignant cell antiproliferative agent.

  For example, compounds of the invention may be calcineurin inhibitors such as cyclosporin A or FK506; mTOR inhibitors such as rapamycin, 40-O- (2-hydroxyethyl) -rapamycin, biolimus-7 or biolimus-9; immunosuppression Ascomycin with properties, such as ABT-281, ASM 981; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; in combination with an IL-1 beta inhibitor Can be used.

  In another embodiment, a compound of the invention is in combination with a co-agent that is a PI3 kinase inhibitor.

  In another embodiment, a compound of the invention is in combination with a co-agent that affects BTK (Bruton-type tyrosine kinase).

  For the treatment of oncology diseases, the compounds of the invention are used in combination with B cell modulators such as rituximab, Btk or Syk inhibitors, PKC, PI3 kinase, PDK, PIM, JAK and mTOR, and BH3 mimetics be able to.

  As used herein, the terms "co-administration" or "combination administration" and the like are intended to encompass the administration of the selected therapeutic agent to a single patient, and the agents may be administered the same It is intended to include treatment regimens that are not necessarily administered by the route or simultaneously.

  The term "pharmaceutical combination" as used herein means a product resulting from a mixture or combination of two or more active ingredients, fixed and not fixed combinations of the above active ingredients Including. The term "fixed combination" means that the active ingredients, eg a compound of formula (I) and a co-agent, are simultaneously administered to the patient in the form of a single entity or administration. The term "non-fixed combination" refers to the active ingredient, for example the compound of formula (I) and the co-agent, both as separate entities simultaneously, simultaneously or sequentially to the patient without specific time limitations. By administering is meant administration that achieves a therapeutically effective level of the two compounds in the patient's body. The latter also applies to cocktail therapies, eg the administration of three or more active ingredients.

  In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent in therapy, as a combined preparation for simultaneous, separate or sequential use. In one embodiment, the treatment is treatment of a MALT1-mediated disease or condition. The product provided as a combined preparation may be formulated as a composition comprising the compound of formula (I) together with another therapeutic agent in the same pharmaceutical composition, or in a separate form, for example in the form of a kit, And a composition comprising the other therapeutic agent.

  In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent. Optionally, as described above, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient.

  In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one of the compositions comprises a compound of formula (I) Do. In one embodiment, the kit comprises means for holding the composition individually, such as a container, a split bottle or a split foil packet. An example of such a kit is a blister pack, which is typically used for the packaging of tablets, capsules and the like.

  The kits of the present invention may be used to administer different dosage forms (eg, oral and parenteral), to administer separate compositions at different dosing intervals, or to titrate separate compositions from one another Can. In order to support compliance, the kits of the present invention typically include instructions for administration.

Claims (15)

A compound of formula (I) or a pharmaceutically acceptable salt thereof;
(In the formula,
R 1 is halogen, cyano or C ₁ -C ₃ alkyl optionally substituted by halogen,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times; C ₁ -C ₆ alkyl, N, N-di-C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkoxy-C _1- C ₆ when a C ₃ -C ₆ cycloalkyl substituted by a alkyl, and / or two of the substituents of the optional one with the atoms to which they are bonded It is in the 1 to 2 ring of 4-6 membered containing O atoms or may form a saturated heterocyclic ring _spirocyclic, C 3 -C _{6 cycloalkyl;} C 1 -C Phenyl optionally substituted by ₆ alkoxy; 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O (the said ring is optionally substituted by amino or hydroxy Optionally substituted by C ₁ -C ₆ alkyl); Rg; or N, N-di-C ₁ -C ₆ alkylaminocarbonyl,
R g is a 5- to 6-membered heterocyclic ring having 1 to 3 hetero atoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ to C ₆ alkyl, optionally substituted by C ₁ -C ₆ alkoxy-carbonyl),
R is phenyl which is independently substituted two or more times by Ra, 2-pyridyl which is independently substituted one or more times by Rb, one or more times independently substituted by Rc 3-pyridyl, or 4-pyridyl independently substituted one or more times by Rd,
Ra is, independently of one another, a 5- to 6-membered having 1 to 2 heteroatoms selected from halogen; cyano; -COOC ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; halogen or N and O C ₁ -C ₆ alkyl optionally substituted by a heterocyclyl ring of the above, said ring being optionally substituted by C ₁ -C ₆ alkyl; ₁ to 3 heteroatoms selected from N and O 5 to 6 membered heteroaryl ring (wherein the ring is C ₁ -C ₆ alkyl optionally substituted by amino, amino or hydroxy, or N-mono- or N, N-di-C ₁ -C ₆ optionally substituted by alkylaminocarbonyl)
And / or two Ra, together with the ring atom to which they are attached, form a 5- to 6-membered heterocyclic or heteroaromatic ring having 1 to 2 N atoms Well, any such ring is optionally substituted by C ₁ -C ₆ alkyl or oxo,
R b, R c and R d independently of one another are halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di -C ₁ -C ₆ alkylamino; halogen or _C 1 -C ₆ alkyl optionally substituted by phenyl; 5-6 membered heteroaryl ring (wherein the ring having 1-3 N atoms, amino or C ₁ -C ₆ alkyl optionally substituted by hydroxy, or optionally substituted by mono- or di-N-C ₁ -C ₆ alkylaminocarbonyl); O-Rh; or Rh,
Rh is a 5-6 membered heterocyclyl ring with 1 to 4 heteroatoms selected from N, O and S, said ring being optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo )). R1 is halogen,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
2-pyridyl independently substituted one or more times by R b, 3-pyridyl independently substituted one or more times independently by R c, or one or more times independently independently by Rd Substituted 4-pyridyl,
Rb, Rc and Rd are as defined in claim 1;
A compound according to claim 1 or a pharmaceutically acceptable salt thereof. R 1 is chloro and the remaining substituents are as defined in claim 1 or 2
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. R1 is chloro,
R is 2-pyridyl independently substituted one or more times by R b, or
Or R is 3-pyridyl independently substituted one or more times by R c, or
Or, R is 4-pyridyl independently substituted one or more times by Rd, R b, R c and R d are as defined in claim 1 and the remaining substituents are as claimed As defined in paragraph 2,
A compound according to claim 2 or a pharmaceutically acceptable salt thereof. R 1 is halogen, cyano or C ₁ -C ₃ alkyl optionally substituted by halogen,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times; C ₁ -C ₆ alkyl, N, N-di-C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkoxy-C _1- a C ₃ -C ₆ cycloalkyl optionally substituted by C ₆ alkyl, or two of the substituents of the optionally it together with the atom to which they are attached Te, 1-2 O atoms 4-6 membered cyclization or may form a saturated heterocyclic ring spirocyclic _containing, C 3 -C _{6 cycloalkyl;} C 1 -C ₆ alkoxy Optionally substituted phenyl; 1 to 3 heteroatoms selected from N and O, optionally substituted by C ₁ -C ₆ alkyl optionally substituted by amino or hydroxy 5-6 membered heteroaryl which is substituted; Rg; or N, N-di-C ₁ -C ₆ alkylaminocarbonyl,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
R is phenyl independently substituted two or more times with Ra,
Cyano, -COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or a 5- to 6-membered heterocyclic ring containing 1-2 N atoms (wherein each Ra is independently of each other, halogen; cyano; Said ring is C ₁ -C ₆ alkyl optionally substituted by C ₁ -C ₆ alkyl) 5-6 membered heteroaryl ring containing 1 to 3 N atoms (The ring is optionally substituted by C ₁ -C ₆ alkyl optionally substituted by amino, amino or hydroxy, or N-mono- or N, N-di-C ₁ -C ₆ alkylaminocarbonyl Yes),
And / or two Ra together with the ring atom to which they are attached form a 5- to 6-membered heterocyclic or heteroaromatic ring containing 1-2 N atoms, such Either ring is optionally substituted by C ₁ -C ₆ alkyl or oxo
A compound according to claim 1 or a pharmaceutically acceptable salt thereof.   The compound according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl. R1 is halogen,
R is phenyl independently substituted two or more times with Ra,
5-, _6- , or 6-membered heterocyclic rings each containing, independently of one another, halogen; cyano; -COOC ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; fluoro or 1 to 2 N atoms C ₁ -C ₆ alkyl optionally substituted by heterocyclyl with C ₁ -C ₆ alkyl; 5- to 6-membered heteroaryl rings containing 1 to 3 N atoms The ring is optionally substituted by C ₁ -C ₆ alkyl optionally substituted by amino, amino or hydroxy, or N-mono- or N, N-di-C ₁ -C ₆ alkylaminocarbonyl ) And
The remaining substituents are as defined in claim 1;
A compound according to claim 1 or 5, or a pharmaceutically acceptable salt thereof. The compound is
(S) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoro) Methyl) -1,2-dihydropyridin-3-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxy-2) -Methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (7- (1-Methoxyethyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea ;
(S) -1- (2-Fluoro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
(S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-cyanopyridin-3-yl) urea;
(S) -1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-methoxy-6- (2H-1,2,2) 3-Triazol-2-yl) pyridin-3-yl) urea;
(S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2-chloropyridin-4-yl) urea;
(S) -Methyl 3-chloro-5- (3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) ureido) benzoate;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methoxypropan-2-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (2-methoxypropan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methylcyclopropyl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1-methylcyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (3-cyano-4- (3-methyl-1H-1,2,4-triazole) 1-yl) phenyl) urea;
1- (3-Chloro-4- (2H-1,2,3-triazol-2-yl) phenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine-6- Il) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] Pyrimidin-6-yl) urea;
1- (5-chloro-6- (4-methyl-2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,1] 5-a] pyrimidin-6-yl) urea;
1- (4- (2-aminopyrimidin-4-yl) -3-chlorophenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-1-methyl-6-oxo-2- (1H-pyrazol-1-yl) -1,6-dihydropyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo) [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-ethoxypyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-bromopyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (6- (1,1-dioxideisothiazolidin-2-yl) -5- (tri) Fluoromethyl) pyridin-3-yl) urea;
1- (3-Chloro-4- (3- (hydroxymethyl) -5-methyl-1H-pyrazol-1-yl) phenyl) -3- (2-chloro-7-iso-propylpyrazolo [1,5] -A] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (1-methyl-1H-pyrazol-5-yl) pyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidine- 6-yl) urea;
1- (2-Chloro-7-isopropyl pyrazolo [1,5-a] pyrimidin-6-yl) -3- (3,5-dichloro-4- (2H-1,2,3-triazole-2-) Yl) phenyl) urea;
1- (5-Chloro-2-oxoindoline-7-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoro-methyl) -1,2-) Dihydropyridin-3-yl) urea;
1- (5-Chloro-2-((1-methylpyrrolidin-3-yl) oxy) -6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- ( 2-chloro-7-isopropyl pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (7- (tert-Butyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-chloro-6- (2H-1,2,3-triazole-2-) Y) pyridin-3-yl) urea;
1- (7- (sec-butyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-chloro-6- (2H-1,2,3-triazole-2-) Y) pyridin-3-yl) urea;
1- (2-Chloro-7- (2-methyltetrahydrofuran-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoro-methyl) pyridin-4-yl )urea;
(R) -1- (2-Chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoro-methyl) pyridine -4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-cyclobutylpyrazolo [1,5-a ] -Pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (2- (2-)) Methoxy-ethoxy) -ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (1- (2-methoxyethoxy) -ethyl) -pyrazolo- [1,5- a) Pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1- (2-methoxyethoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl)- Pyridin-4-yl) urea;
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (2- (2-)) Methoxy-ethoxy) -ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,4-dioxane-2-yl) )-Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxypropane-) 2-yl) -pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxypropane-) 2-yl) -pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) -Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) -pyridin-4-yl )urea;
(R) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (1-methyl-2-oxo-5- (trifluoro) Methyl) -1,2-dihydropyridin-3-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (methoxy (phenyl) methyl) -pyrazolo [ 1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methoxymethyl) cyclobutyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1- (methoxymethyl) cyclobutyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea ;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-cyclopropylpyrazolo [1,5-a ] Pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methoxyphenyl) pyrazolo [1,1] 5-a] pyrimidin-6-yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (tetrahydrofuran-2-yl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methyltetrahydro-2H-pyran) 4-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxyethyl) pyrazolo [ 1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (tetrahydrofuran-3-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (tetrahydro-2H-pyran-4-yl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (methoxymethyl) pyrazolo [1,5- a) Pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((tetrahydro-2H-pyran-4-) (I) methyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (isopropoxymethyl) pyrazolo [1,5] -A] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-methylpyrazolo [1,5-a] pyrimidine- 6-yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (furan-2-yl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,3-dimethoxypropyl) pyrazolo [ 1,5-a] pyrimidin-6-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (7- (1- (benzyloxy) ) Ethyl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) urea;
tert-Butyl 2- (2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ureido) pyrazolo [1,5 -A] pyrimidin-7-yl) morpholine-4-carboxylate;
1- (7- (3-oxabicyclo [3.1.0] hexan-6-yl) -2-chloropyrazolo [1,5-a] pyrimidin-6-yl) -3- (5-chloro-6-) Methoxypyridin-3-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (5-oxaspiro [2.4] heptane) -1-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (pyridin-4-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
2-chloro-6- (3- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) ureido) -N, N-dimethylpyrazolo [1,1 5-a] pyrimidine-7-carboxamide;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (7- (1-methoxyethyl) -2-methyl -Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-methyl-7- (1-methylcyclopropyl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-methyl-7- (1-methylcyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methoxy-2) -Methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxy-2-methylpropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine- 4-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methoxymethyl) cyclopropyl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1- (methoxymethyl) cyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (7- (1- (methoxymethyl) cyclopropyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (7- (1- (Methoxymethyl) cyclopropyl) -2-methylpyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea ;
1- (2-Chloro-7- (2- (tetrahydro-2H-pyran-4-yl) propan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (2- (2) Trifluoromethyl) pyridin-4-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxypropane-2-) Yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (2- (2-)) (Dimethylamino) ethoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((4-methylmorpholin-3-yl) ) Methyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methylpiperidine-) 2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-((R) ) -2-Methoxy-propoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1-methyl-1H-imidazole-2) -Yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6-methoxypyridin-3-yl) -3- (2-chloro-7- (5-methyltetrahydrofuran-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) cyclopropyl)) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5- (difluoromethyl) -6- (2H-1) 2,3-Triazol-2-yl) pyridin-3-yl) urea;
1- (2-Chloro-7- (methoxy (tetrahydro-2H-pyran-4-yl) methyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridine -4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2- (methoxymethyl) tetrahydrofuran-2) -Yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (difluoromethyl) pyridin-4-yl) urea ;
(S) -1- (5-Chloro-6- (difluoromethoxy) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidine-6 -Yl) urea;
(S) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-fluoro-7- (1) -Methoxy-ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-fluoro-7- (1-methoxyethyl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-cyano-7- (1-methoxy-ethyl) ) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (difluoromethoxy) pyridin-3-yl) -3- (2-chloro-7- (1- (2-methoxyethoxy) ethyl) pyrazolo [1,5- a) Pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((1R, 2R) -1,2) -Dimethoxy-propyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-2- (2- (dimethylamino) ethoxy) pyridin-3-yl) -3- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5- a) Pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( R) -Tetrahydro-furan-3-yl) oxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( S) -Tetrahydro-furan-3-yl) oxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( S) -Tetrahydro-furan-3-yl) methoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7-((S) -1-(((( R) -Tetrahydro-furan-3-yl) methoxy) ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-methyl-7- (2-methyltetrahydrofuran-2-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-chloro-7- (1-methoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2-cyanopyridin-4-yl) urea;
1- (2-Chloro-7- (2- (methoxymethyl) tetrahydrofuran-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (5- (trifluoromethyl) pyridine-3 -Yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethyl-) Amino) cyclopropyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxy) -Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (2-Chloro-7- (1,2-dimethoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
(S) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxy-propan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Methoxy-propan-2-yl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5- (2H-1,2,3-triazol-2-yl) -2- (trifluoromethyl) pyridin-4-yl) -3- (2-chloro-7-isopropylpyrazolo [1,1] 5-a] pyrimidin-6-yl) urea;
(R) -1- (6- (2H-1,2,3-triazol-2-yl) -5- (trifluoromethyl) pyridin-3-yl) -3- (2-chloro-7- (1) -Hydroxy-ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (2-Chloro-7- (1-hydroxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) -3- (2- (trifluoromethyl) pyridin-4-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-2-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methylmorpholin-2-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (4- (4- (aminomethyl) -1H-pyrazol-1-yl) -3-chlorophenyl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6- Il) urea;
1- (6- (4- (aminomethyl) -1H-pyrazol-1-yl) -5-chloropyridin-3-yl) -3- (2-chloro-7-isopropylpyrazolo [1,5-a ] Pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (methylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
2- (3- (2-Chloro-7-isopropylpyrazolo [1,5-a] pyrimidin-6-yl) ureido) -4- (trifluoromethyl) pyridine 1-oxide;
(R) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1- (dimethylamino) ) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (morpholin-3-yl) pyrazolo [1 5-a] pyrimidin-6-yl) urea;
(S) -1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (2-methyl-1) -(Methyl-amino) propyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea;
1- (5-Chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (4-methylmorpholin-3-yl) Pyrazolo [1,5-a] pyrimidin-6-yl) urea;
(R) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) -3- (2-chloro-7- (1,2-dimethoxy) Ethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea; and (S) -1- (5-chloro-6- (2H-1,2,3-triazol-2-yl) pyridine-3 4. A compound according to claim 1, especially selected from: -yl) -3- (2-chloro-7- (1,2-dimethoxyethyl) pyrazolo [1,5-a] pyrimidin-6-yl) urea. Pharmaceutically acceptable salts thereof. R1 is fluoro,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , phenyl or _C 1 -C ₆ alkoxy (said _alkoxy, C 1 -C case may be substituted by a ₆ alkoxy or Rg, or phenyl) by, _{C 1} optionally substituted by one or more times, ~ C ₆ alkyl,
A 5- to 6-membered heterocyclic ring wherein Rg is selected from N and O having 1 to 3 hetero atoms (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ to C ₆ alkyl, optionally substituted by C ₁ -C ₆ alkoxy-carbonyl),
R is 2-pyridyl substituted one or more times with R b,
R b independently of one another of halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di-C _1- C ₆ alkylamino; C _{1 to} C ₆ alkyl optionally substituted by halogen or phenyl; 5 to 6 membered heteroaryl ring having 1 to 3 N atoms (the said ring is optionally substituted by amino or hydroxy A substituted C ₁ -C ₆ alkyl, or optionally substituted by mono- or di-N-C ₁ -C ₆ alkylaminocarbonyl); O-Rh; or Rh,
A 5- to 6-membered heterocyclyl ring with 1 to 4 heteroatoms selected from N, O and S, wherein said ring is optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo ),
A compound according to claim 1 or a pharmaceutically acceptable salt thereof. R1 is fluoro,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
R is 3-pyridyl which is substituted one or more times by R c,
R c independently of one another of halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di-C _1- C ₆ alkylamino; C _{1 to} C ₆ alkyl optionally substituted by halogen or phenyl; 5 to 6 membered heteroaryl ring having 1 to 3 N atoms (the said ring is optionally substituted by amino or hydroxy A substituted C ₁ -C ₆ alkyl, or optionally substituted by mono- or di-N-C ₁ -C ₆ alkylaminocarbonyl); O-Rh; or Rh,
5- to 6-membered heterocyclyl having 1 to 4 heteroatoms, wherein Rh is selected from N, O and S (the said ring is optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo) Is
A compound according to claim 1 or a pharmaceutically acceptable salt thereof. R1 is fluoro,
R 2 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, hydroxyl, N, N-di-C ₁ -C ₆ alkylamino, N-mono-C ₁ -C ₆ alkylamino, O-Rg, Rg , Phenyl or C ₁ -C ₆ alkoxy (the said alkoxy is also C ₁ -C ₆ alkoxy, N, N-di-C ₁ -C ₆ alkylamino, optionally substituted by R g or phenyl) , C ₁ -C ₆ alkyl which is optionally substituted one or more times,
5- to 6-membered heterocyclic ring wherein Rg contains 1 to 3 heteroatoms selected from N and O (the ring is a C _{1 to} C ₆ alkyl, C _{1 to} C ₆ alkoxy-C ₁ To C ₆ alkyl, optionally substituted by C _{1 to} C ₆ alkoxy-carbonyl),
R is 4-pyridyl substituted one or more times by Rd,
Rd is, independently of one another, halogen; oxo; hydroxyl; cyano; C ₁ -C ₆ alkoxy optionally substituted by halogen; C ₁ -C ₆ alkoxycarbonyl; phenyl; N, N-di-C _1- C ₆ alkylamino; C _{1 to} C ₆ alkyl optionally substituted by halogen or phenyl; 5 to 6 membered heteroaryl ring containing 1 to 3 N atoms (the said ring is optionally substituted by amino or hydroxy _C 1 -C ₆ alkyl or mono-, substituted by - optionally substituted by or di _-N-C 1 ~C ₆ alkylaminocarbonyl); a or Rh,; O-Rh
5 to 6 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O and S (wherein the ring is optionally substituted by C _{1 to} C ₆ alkyl, hydroxyl or oxo) ),
A compound according to claim 1 or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11 and one or more pharmaceutically acceptable carriers. A compound according from 請 Motomeko 1 in any one of 11, or a pharmaceutically includes acceptable salts thereof, it is used one or more treatment active coagent paired see fit, pharmaceutical compositions . A pharmaceutical composition for modulating the MALT1 activity in a subject,請 compound according to any one of Motomeko 1 to 11, or a pharmaceutically acceptable including pharmaceutical compositions thereof salts. A compound according to any one of 請 Motomeko 1 to 11, or a pharmaceutically acceptable salt thereof, MALT1 inhibitor.